U.S. patent number 9,856,262 [Application Number 15/302,588] was granted by the patent office on 2018-01-02 for analogues of 4h-pyrazolo[1,5-a] benzimidazole compound as parp inhibitors.
This patent grant is currently assigned to Hubei Bio-Pharmaceutical Industrial Technological Institute Inc., Humanwell Healthcare (Group) Co., Ltd., Medshine Discovery Inc.. The grantee listed for this patent is HUBEI BIO-PHARMACEUTICAL INDUSTRIAL TECHNOLOGICAL INSTITUTE INC., HUMANWELL HEALTHCARE (GROUP) CO., LTD., MEDSHINE DISCOVERY INC.. Invention is credited to Hailiang Chen, Shuhui Chen, Zhaozhong Ding, Lu Huang, Gang Li, Lie Li, Wenjie Sun, Ronghua Tu, Cailin Wang, Xuehai Wang, Yong Xu, Yang Yue, Zhibo Zhang.
United States Patent |
9,856,262 |
Wang , et al. |
January 2, 2018 |
Analogues of 4H-pyrazolo[1,5-a] benzimidazole compound as PARP
inhibitors
Abstract
Disclosed is a series of analogs of
4H-pyrazolo[1,5-.alpha.]benzimidazole compound as PARP inhibitors.
In particular, disclosed in the invention is a compound as shown by
formula (I) or a pharmaceutically acceptable salt thereof as a PARP
inhibitor.
Inventors: |
Wang; Xuehai (Wuhan,
CN), Ding; Zhaozhong (Shanghai, CN), Xu;
Yong (Wuhan, CN), Chen; Shuhui (Shanghai,
CN), Li; Lie (Wuhan, CN), Li; Gang
(Shanghai, CN), Tu; Ronghua (Wuhan, CN),
Wang; Cailin (Shanghai, CN), Yue; Yang (Wuhan,
CN), Zhang; Zhibo (Shanghai, CN), Chen;
Hailiang (Wuhan, CN), Sun; Wenjie (Wuhan,
CN), Huang; Lu (Wuhan, CN) |
Applicant: |
Name |
City |
State |
Country |
Type |
HUBEI BIO-PHARMACEUTICAL INDUSTRIAL TECHNOLOGICAL INSTITUTE
INC.
HUMANWELL HEALTHCARE (GROUP) CO., LTD.
MEDSHINE DISCOVERY INC. |
Wuhan, Hubei
Wuhan, Hubei
Nanjing, Jiangsu |
N/A
N/A
N/A |
CN
CN
CN |
|
|
Assignee: |
Hubei Bio-Pharmaceutical Industrial
Technological Institute Inc. (Wuhan, Hubei, CN)
Humanwell Healthcare (Group) Co., Ltd. (Wuhan, Hubei,
CN)
Medshine Discovery Inc. (Nanjing, Jiangsu,
CN)
|
Family
ID: |
54287319 |
Appl.
No.: |
15/302,588 |
Filed: |
March 30, 2015 |
PCT
Filed: |
March 30, 2015 |
PCT No.: |
PCT/CN2015/075363 |
371(c)(1),(2),(4) Date: |
October 07, 2016 |
PCT
Pub. No.: |
WO2015/154630 |
PCT
Pub. Date: |
October 15, 2015 |
Prior Publication Data
|
|
|
|
Document
Identifier |
Publication Date |
|
US 20170029430 A1 |
Feb 2, 2017 |
|
Foreign Application Priority Data
|
|
|
|
|
Apr 10, 2014 [CN] |
|
|
2014 1 0144173 |
Mar 13, 2015 [CN] |
|
|
2015 1 0113090 |
|
Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61P
9/00 (20180101); A61P 25/00 (20180101); A61P
3/10 (20180101); A61P 29/00 (20180101); A61P
35/00 (20180101); C07D 487/04 (20130101); A61P
9/10 (20180101); A61P 43/00 (20180101); C07D
519/00 (20130101) |
Current International
Class: |
C07D
487/04 (20060101); C07D 519/00 (20060101) |
References Cited
[Referenced By]
U.S. Patent Documents
Foreign Patent Documents
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|
104974161 |
|
Oct 2015 |
|
CN |
|
2656843 |
|
Oct 2013 |
|
EP |
|
2009541346 |
|
Nov 2009 |
|
JP |
|
WO-2007076127 |
|
Jul 2007 |
|
WO |
|
WO-2007/149907 |
|
Dec 2007 |
|
WO |
|
WO-2007144669 |
|
Dec 2007 |
|
WO |
|
WO-2008090379 |
|
Jul 2008 |
|
WO |
|
WO-2013164061 |
|
Nov 2013 |
|
WO |
|
WO-2013174822 |
|
Nov 2013 |
|
WO |
|
WO-2013182580 |
|
Dec 2013 |
|
WO |
|
WO-2014009872 |
|
Jan 2014 |
|
WO |
|
WO-2014019468 |
|
Feb 2014 |
|
WO |
|
WO-2014023390 |
|
Feb 2014 |
|
WO |
|
Other References
Helen E. Bryant, etc., Specific killing of BRCA2-deficient tumours
with inhibitors of poly(ADP-ribose) polymerase; Nature 434, 913-917
(2005). cited by applicant .
Dana V. Ferraris; Evolution of Poly(ADP-ribose) Polymerase-1
(PARP-1) Inhibitors. From Concept to Clinic; J. Med. Chem. 2010,
53, 4561-4584. cited by applicant .
Laszlo Virag et al.; The Therapeutic Potential of Poly(ADP-Ribose)
Polymerase Inhibitors; Pharmacol Rev 54:375-429, 2002. cited by
applicant .
Stephen M. Berge, etc.; Pharmaceutical Salts; Journal of
Pharmaceutical Sciences vol. 66, No. 1, Jan. 1977, 1-19. cited by
applicant .
Hubert Maehr; A Proposed Hew Convention for Graphic Presentation of
Molecular Geometry and Topography; Journal of Chemical Education
vol. 62 No. 2 Feb. 1985. cited by applicant .
Remington:The Science and Practice of Pharmacy, 21st Ed.,
Lippincott, Williams &Wilkins (2005). cited by applicant .
Chinese Priority Application No. 201510113090.X--English
translation. cited by applicant .
First Office Action issued in SG11201608438Y. cited by applicant
.
First Office Action issued in JP2017-504223. cited by applicant
.
Second OA issued in AU2015245786. cited by applicant .
Wang et al. Design and Synthesis of New Templates Derived from
Pyrrolopyrimidine as Selective Multidrug-Resistance-Associated
Protein Inhibitors in Multidrug Resistance; J. Med. Chem. 2004, 47,
1339-1350. cited by applicant .
Tong et al. Synthesis and Evaluation of a New Generation of Orally
Efficacious Benzimidazole-Based Poly(ADP-ribose) Polymerase-1
(PARP-1) Inhibitors as Anticancer Agents; J. Med. Chem. 2009, 52,
6803-6813. cited by applicant.
|
Primary Examiner: Shterengarts; Samantha
Attorney, Agent or Firm: Harness, Dickey & Pierce
P.L.C.
Claims
What is claimed is:
1. A compound of formula (I) or a pharmaceutically acceptable salt
thereof, ##STR00340## wherein, D is selected from the group
consisting of --C(R.sub.d1)(R.sub.d2)--, --C(.dbd.O)N(R.sub.d3)--,
--N(R.sub.d4)--, --C(.dbd.NR.sub.d5)--,
--S(.dbd.O).sub.2N(R.sub.d6)--, --S(.dbd.O) N(R.sub.d7)--, --O--,
--S--, --C(.dbd.O)O--, --C(.dbd.O)--, --C(.dbd.S)--, --S(.dbd.O)--,
and --S(.dbd.O).sub.2--; R.sub.1-3, R.sub.d1, and R.sub.d2 are
separately and independently selected from the group consisting of
H, F, Cl, Br, I, CN, OH, SH, and NH.sub.2, or selected from the
group, optionally substituted by R.sub.01, consisting of C.sub.1-10
alkyl, C.sub.1-10 heteroalkyl, C.sub.3-10 cyclohydrocarbyl,
C.sub.3-10 heterocyclohydrocarbyl, C.sub.1-10 alkyl substituted by
C.sub.3-10 cyclohydrocarbyl or C.sub.3-10 heterocyclohydrocarbyl,
and C.sub.1-10 heteroalkyl substituted by C.sub.3-10
cyclohydrocarbyl or C.sub.3-10 heterocyclohydrocarbyl; R.sub.01 is
selected from the group consisting of F, Cl, Br, I, CN, OH, SH,
NH.sub.2, and R.sub.02; R.sub.02 is selected from the group
consisting of C.sub.1-10 alkyl, C.sub.1-10 alkylamino,
N,N-di(C.sub.1-10 alkyl) amino, C.sub.1-10 alkyloxyl, C.sub.1-10
alkylacyl, C.sub.1-10 alkyloxylcarbonyl, C.sub.1-10 alkylsulfonyl,
C.sub.1-10 alkylsulfinyl, C.sub.3-10 cycloalkyl, C.sub.3-10
cycloalkylamino, C.sub.3-10 heterocycloalkylamino, C.sub.3-10
cycloalkyloxyl, C.sub.3-10 cycloalkylacyl, C.sub.3-10
cycloalkyloxylcarbonyl, C.sub.3-10 cycloalkylsulfonyl, and
C.sub.3-10 cycloalkylsulfinyl; heteroatom or heteroatomic group is
separately and independently selected from the group consisting of
--C(.dbd.O)N(R.sub.d3)--, --N(R.sub.d4)--, --C(.dbd.NR.sub.d5)--,
--S(.dbd.O).sub.2N(R.sub.d6)--, --S(.dbd.O) N(R.sub.d7)--, --O--,
--S--, --C(.dbd.O)O--, --C(.dbd.O)--, --C(.dbd.S)--, --S(.dbd.O)--,
and/or --S(.dbd.O).sub.2--; R.sub.d3-d7 are separately and
independently selected from the group consisting of H, and
R.sub.03; R.sub.03 is selected from the group consisting of
C.sub.1-10 alkyl, C.sub.1-10 alkylacyl, C.sub.1-10
alkyloxylcarbonyl, C.sub.1-10 alkylsulfonyl, C.sub.1-10
alkylsulfinyl, C.sub.3-10 cycloalkyl, C.sub.3-10 cycloalkylacyl,
C.sub.3-10 cycloalkyloxylcarbonyl, C.sub.3-10 cycloalkylsulfonyl,
and C.sub.3-10 cycloalkylsulfinyl; R.sub.02, and R.sub.03 are
optionally substituted by R.sub.001; R.sub.001 is selected from the
group consisting of F, Cl, Br, I, CN, OH, N(CH.sub.3).sub.2,
NH(CH.sub.3), NH.sub.2, CF.sub.3, (NH.sub.2)CH.sub.2, (HO)CH.sub.2,
CH.sub.3, CH.sub.3O, CH.sub.3C(.dbd.O), CH.sub.3O C(.dbd.O),
CH.sub.3S(.dbd.O).sub.2, and CH.sub.3S(.dbd.O); and the number of
R.sub.01, R.sub.001, the heteroatom, or heteroatomic group is
separately and independently selected from 0, 1, 2, and 3.
2. The compound of claim 1 or a pharmaceutically acceptable salt
thereof, wherein the D is selected from --NH--, --N(CH.sub.3)--,
--C(F).sub.2--, --C(H) (F)-- and --C(H)(OH)--.
3. The compound of claim 1 or 2, or a pharmaceutically acceptable
salt thereof, wherein R.sub.1-3 are separately and independently
selected from the group consisting of H, F, Cl, Br, I, CN, OH, SH,
NH.sub.2, C.sub.1-6 alkyl, C.sub.1-6 alkyloxyl, benzyloxyl,
--CH.sub.2N(R.sub.21)(R.sub.22), ##STR00341## in which, L and
D.sub.21 are separately and independently selected from the group
consisting of --C(R.sub.d1)(R.sub.d2)--, --C(.dbd.O)N(R.sub.d3)--,
--N(R.sub.d4)--, --C(.dbd.NR.sub.d6)--,
--S(.dbd.O).sub.2N(R.sub.d6)--, --S(.dbd.O) N(R.sub.d7)--, --O--,
--S--, --C(.dbd.O)--, --C(.dbd.O)O--, --C(.dbd.S)--, --S(.dbd.O)--,
and --S(.dbd.O).sub.2--; L may also be a single bond for a linkage
purpose only; T.sub.21-22 are separately and independently selected
from the group consisting of C(R.sub.t) and N; X is selected from
(CH2).sub.n optionally substituted by R.sub.01, and n is selected
from 0, 1, 2, or 3; Y is selected from (CH2).sub.m optionally
substituted by R.sub.01, and m is selected from 0, 1, 2, or 3;
R.sub.21-23 and R.sub.d3-d7 are separately and independently
selected from the group consisting of H and R.sub.03; R.sub.24-27,
R.sub.d1, R.sub.d2, and R.sub.t are separately and independently
selected from the group consisting of H, F, Cl, Br, I, CN, OH, SH,
and NH.sub.2, or selected from the group, optionally substituted by
R.sub.01, consisting of C.sub.1-10alkyl, C.sub.1-10 heteroalkyl,
C.sub.3-10 cyclohydrocarbyl, C.sub.3-10 heterocyclohydrocarbyl,
C.sub.1-10 alkyl substituted by C.sub.3-10 cyclohydrocarbyl or
C.sub.3-10 heterocyclohydrocarbyl, and C.sub.1-10 heteroalkyl
substituted by C.sub.3-10 cyclohydrocarbyl or C.sub.3-10
heterocyclohydrocarbyl; R.sub.01 is selected from the group
consisting of F, Cl, Br, I, CN, OH, SH, NH.sub.2, and R.sub.02;
R.sub.02 is selected from the group consisting of C.sub.1-10alkyl,
C.sub.1-10alkylamino, N,N-di(C.sub.1-10alkyl) amino, C.sub.1-10
alkyloxyl, C.sub.1-10 alkylacyl, C.sub.1-10 alkyloxylcarbonyl,
C.sub.1-10 alkylsulfonyl, C.sub.1-10 alkylsulfinyl, C.sub.3-10
cycloalkyl, C.sub.3-10 cycloalkylamino, C.sub.3-10
heterocycloalkylamino, C.sub.3-10 cycloalkyloxyl, C.sub.3-10
cycloalkylacyl, C.sub.3-10 cycloalkyloxylcarbonyl, C.sub.3-10
cycloalkylsulfonyl, and C.sub.3-10 cycloalkylsulfinyl; the
heteroatom or heteroatomic group is separately and independently
selected from the group consisting of --C(.dbd.O)N(R.sub.d3)--,
--N(R.sub.d4)--, --C(.dbd.NR.sub.d5)--,
--S(.dbd.O).sub.2N(R.sub.d6)--, --S(.dbd.O)N(R.sub.d7)--, --O--,
--S--, --C(.dbd.O)O--, --C(.dbd.O)--, --C(.dbd.S)--, --S(.dbd.O)--,
and/or --S(.dbd.O).sub.2--; R.sub.d3-d7 are separately and
independently selected from the group consisting of H, and
R.sub.03; R.sub.03 is selected from the group consisting of
C.sub.1-10alkyl, C.sub.1-10alkylacyl, C.sub.1-10alkyloxylcarbonyl,
C.sub.1-10 alkylsulfonyl, C.sub.1-10alkylsulfinyl, C.sub.3-10
cycloalkyl, C.sub.3-10 cycloalkylacyl, C.sub.3-10
cycloalkyloxylcarbonyl, C.sub.3-10 cycloalkylsulfonyl, and
C.sub.3-10 cycloalkylsulfinyl; R.sub.02, and R.sub.03 are
optionally substituted by R.sub.001; R.sub.001 is selected from the
group consisting of F, Cl, Br, I, CN, OH, N(CH.sub.3).sub.2,
NH(CH.sub.3), NH.sub.2, CF.sub.3, (NH.sub.2)CH.sub.2, (HO)CH.sub.2,
CH.sub.3, CH.sub.3O, HC(.dbd.O), CH.sub.3O C(.dbd.O),
CH.sub.3S(.dbd.O).sub.2, and CH.sub.3S(.dbd.O); and the number of
R.sub.01, R.sub.001, the heteroatom, or heteroatomic group is
separately and independently selected from 0, 1, 2, or 3.
4. The compound of claim 3 or a pharmaceutically acceptable salt
thereof, wherein the R.sub.1 and R.sub.3 are separately and
independently selected from the group consisting of H, F, Cl, Br,
I, CN, OH, SH, NH.sub.2, C.sub.1-3 alkyl, C.sub.1-3 alkyloxyl,
benzyloxyl, and ##STR00342## in which R.sub.101 is selected from
the group consisting of H, methyl, ethyl, n-propyl, or
isopropyl.
5. The compound of claim 3 or a pharmaceutically acceptable salt
thereof, wherein R.sub.2 is selected from
--CH.sub.2N(R.sub.201)(R.sub.202), in which R.sub.201 and R.sub.202
are separately and independently selected from the group consisting
of H, C.sub.1-3 alkyl, C.sub.1-3 alkylacyl, C.sub.3-6
cycloalkylacyl, or C.sub.3-6 cycloalkyl.
6. The compound of claim 3 or a pharmaceutically acceptable salt
thereof, wherein R.sub.2 is selected from the group consisting of
##STR00343## in which R.sub.203, R.sub.204, R.sub.217, and
R.sub.218 are separately and independently selected from the group
consisting of H, substituted or unsubstituted C.sub.1-3 alkyl,
cyclopropyl, or cyclopropylmethylene, the substituent is selected
from the group consisting of F, Cl, Br, I, CN, OH, NH.sub.2,
methyl, or methyloxyl, and the number of substituents is 0, 1, 2,
or 3.
7. The compound of claim 3 or a pharmaceutically acceptable salt
thereof, wherein R.sub.2 is selected from ##STR00344## in which
R.sub.205 and R.sub.206 are separately and independently selected
from the group consisting of H, substituted or unsubstituted
C.sub.1-3 alkyl, cyclopropyl, and cyclopropylmethylene, wherein the
substituent is selected from the group consisting of F, Cl, Br, I,
CN, OH, NH.sub.2, methyl, or methyloxyl, and the number of
substituents is 0, 1, 2, or 3.
8. The compound of claim 3 or a pharmaceutically acceptable salt
thereof, wherein R.sub.2 is selected from ##STR00345## in which
R.sub.207 is selected from the group consisting of H, substituted
or unsubstituted C.sub.1-3 alkyl, cyclopropyl,
cyclopropylmethylene, cyclobutyl, cyclobutylmethylene,
oxacyclobutyl or oxacyclobutylalkylene, where the substituent is
selected from the group consisting of F, Cl, Br, I, CN, OH,
NH.sub.2, methyl, CF.sub.3, methyloxyl, and methylsulfonyl, and the
number of substituents is 0, 1, 2, or 3.
9. The compound of claim 3 or a pharmaceutically acceptable salt
thereof, wherein R.sub.2 is selected from the group consisting of
##STR00346## in which R.sub.208 is selected from the group
consisting of H, substituted or unsubstituted C.sub.1-4 alkyl,
wherein the substituent is selected from the group consisting of F,
Cl, Br, I, CN, OH, NH.sub.2, methyl, CF.sub.3, methyloxyl, and
methylsulfonyl, and the number of substituents is 0, 1, 2, or
3.
10. The compound of claim 3 or a pharmaceutically acceptable salt
thereof, wherein R.sub.2 is selected from ##STR00347## in which
R.sub.209 is selected from the group consisting of
--C(R.sub.d1)(R.sub.d2)--, --C(.dbd.O)N(R.sub.d3)--,
--N(R.sub.d4)--, --C(.dbd.NR.sub.d6)--,
--S(.dbd.O).sub.2N(R.sub.d6)--, --S(.dbd.O) N(R.sub.d7)--, --O--,
--S--, --C(.dbd.O)O--, --C(.dbd.O)--, --C(.dbd.S)--, --S(.dbd.O)--,
or --S(.dbd.O).sub.2--, R.sub.d1-d7 are as defined in claim 1.
11. The compound of claim 3 or a pharmaceutically acceptable salt
thereof, wherein R.sub.2 is selected from ##STR00348## in which
R.sub.210 is selected from the group consisting of H, F, Cl, Br, I,
CN, OH, NH.sub.2, N,N-di(C.sub.1-3 alkyl)amino, and C.sub.1-3
alkylamino.
12. The compound of claim 3 or a pharmaceutically acceptable salt
thereof, wherein R.sub.2 is selected from ##STR00349## in which
R.sub.211-214 are selected from the group consisting of H or
substituted or unsubstituted C.sub.1-4 alkyloxylcarbonyl, C.sub.1-4
alkyl, C.sub.3-6 cycloalkyl, C.sub.3-6 cycloalkylmethylene, or
unsaturated C.sub.5-6 heterocyclohydrocarbyl, R.sub.211-213 are
also selected from the group consisting of F, Cl, Br, I, CN, OH,
and NH.sub.2, the cycloalkyl or unsaturated heterocyclohydrocarbyl
has O, S or NR.sub.216 with a number of 0, 1 or 2; R.sub.216 is
selected from the group consisting of H and C.sub.1-4alkyl
substituted by R.sub.215, R.sub.215 is selected from the group
consisting of F, Cl, Br, I, CN, OH, NH.sub.2, methyl, ethyl,
methyloxyl, ethyloxyl, formyl, acetyl, methylsulfonyl,
ethylsulfonyl, methyloxylcarbonyl, ethyloxylcarbonyl,
dimethylamino, diethylamino, dimethylaminocarbonyl,
diethylaminocarbonyl, oxo, the number of R.sub.215 is 1, 2, or
3.
13. The compound of claim 3 or a pharmaceutically acceptable salt
thereof, wherein R.sub.2 is selected from ##STR00350## in which T22
is selected from the group consisting of N or C(R.sub.224),
R.sub.220-224 are separately and independently selected from the
group consisting of H, F, Cl, Br, I, CN, OH, SH, NH.sub.2,
C.sub.1-3 alkylamino-C.sub.1-3 alkyl, and ##STR00351##
14. The compound of claim 1 or a pharmaceutically acceptable salt
thereof, wherein the compound is selected from the group consisting
of: 1)
6-fluoro-3-(piperidin-4-yl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carb-
oxamide; 2)
3-(1-ethylpiperidin-4-yl)-6-fluoro-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8--
carboxamide; 3)
6-fluoro-3-(1-(2-fluoroethyl)piperidin-4-yl)-4H-benzo[4,5]imidazo[1,2-b]p-
yrazole-8-carboxamide; 4)
3-(1-cyclopropylpiperidin-4-yl)-6-fluoro-4H-benzo[4,5]imidazo[1,2-b]pyraz-
ole-8-carboxamide; 5)
3-(1-(cyclopropylmethyl)piperidin-4-yl)-6-fluoro-4H-benzo[4,5]imidazo[1,2-
-b]pyrazole-8-carboxamide; 6)
6-fluoro-3-(1-(2-hydroxy-2-methylpropyl)piperidin-4-yl)-4H-benzo[4,5]imid-
azo[1,2-b]pyrazole-8-carboxamide; 7)
6-fluoro-3-(1-(2-fluoro-2-methylpropyl)piperidin-4-yl)-4H-benzo[4,5]imida-
zo[1,2-b]pyrazole-8-carboxamide; 8)
3-(1-(cyclopropanecarbonyl)piperidin-4-yl)-6-fluoro-4H-benzo[4,5]imidazo[-
1,2-b]pyrazole-8-carboxamide; 9)
6-fluoro-3-(1-methylpiperidin-4-yl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-
-carboxamide; 10)
6-fluoro-3-(1-isopropylpiperidin-4-yl)-4H-benzo[4,5]imidazo[1,2-b]pyrazol-
e-8-carboxamide; 11)
6-fluoro-3-(1-(oxetan-3-yl)piperidin-4-yl)-4H-benzo[4,5]imidazo[1,2-b]pyr-
azole-8-carboxamide; 12)
6-fluoro-3-(1-propylpiperidin-4-yl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-
-carboxamide; 13)
3-(1-(2-aminoethyl)piperidin-4-yl)-6-fluoro-4H-benzo[4,5]imidazo[1,2-b]py-
razole-8-carboxamide; 14)
3-(1-(2-(dimethylamino)ethyl)piperidin-4-yl)-6-fluoro-4H-benzo[4,5]imidaz-
o[1,2-b]pyrazole-8-carboxamide; 15)
6-fluoro-3-(1-(2-methoxyethyl)piperidin-4-yl)-4H-benzo[4,5]imidazo[1,2-b]-
pyrazole-8-carboxamide; 16)
6-fluoro-3-(1-(2-hydroxyethyl)piperidin-4-yl)-4H-benzo[4,5]imidazo[1,2-b]-
pyrazole-8-carboxamide; 17)
3-(1-ethylpiperidin-3-yl)-6-fluoro-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8--
carboxamide; 18)
3-(1-ethylazepan-4-yl)-6-fluoro-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-car-
boxamide; 19)
6-fluoro-3-(1-methylazepan-4-yl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-ca-
rboxamide; 20)
6-fluoro-3-(1-methylpyrrolidin-3-yl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole--
8-carboxamide; 21)
3-(1-ethylpyrrolidin-3-yl)-6-fluoro-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-
-carboxamide; 22)
6-fluoro-3-(1-isopropylpyrrolidin-3-yl)-4H-benzo[4,5]imidazo[1,2-b]pyrazo-
le-8-carboxamide; 23)
6-fluoro-3-(pyrrolidin-2-yl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carbox-
amide; 24)
6-fluoro-3-(1-propylpyrrolidin-2-yl)-4H-benzo[4,5]imidazo[1,2-b-
]pyrazole-8-carboxamide;
6-fluoro-3-(1-methylpyrrolidin-2-yl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole--
8-carboxamide; 25)
3-(1-ethylpyrrolidin-2-yl)-6-fluoro-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-
-carboxamide; 26)
3-(1-ethylpiperidin-4-yl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxami-
de; 27)
6-fluoro-3-(1-propylpyrrolidin-2-yl)-4H-benzo[4,5]imidazo[1,2-b]py-
razole-8-carboxamide; 28)
6-fluoro-3-(3-methyl-3-azabicyclo[3.1.0]hexan-1-yl)-4H-benzo[4,5]imidazo[-
1,2-b]pyrazole-8-carboxamide; 29)
3-(3-ethyl-3-azabicyclo[3.1.0]hexan-1-yl)-6-fluoro-4H-benzo[4,5]imidazo[1-
,2-b]pyrazole-8-carboxamide; 30)
3-(3-cyclobutyl-3-azabicyclo[3.1.0]hexan-1-yl)-6-fluoro-4H-benzo[4,5]imid-
azo[1,2-b]pyrazole-8-carboxamide; 31)
3-(3-(cyclopropylmethylene)-3-azabicyclo[3.1.0]hexan-1-yl)-6-fluoro-4H-be-
nzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide; 32)
6-fluoro-3-(3-isopropyl-3-azabicyclo[3.1.0]hexan-1-yl)-4H-benzo[4,5]imida-
zo[1,2-b]pyrazole-8-carboxamide; 33)
3-(3-azabicyclo[3.1.0]hexan-6-yl)-6-fluoro-4H-benzo[4,5]imidazo[1,2-b]pyr-
azole-8-carboxamide; 34)
3-(3-ethyl-3-azabicyclo[3.1.0]hexan-6-yl)-6-fluoro-4H-benzo[4,5]imidazo[1-
,2-b]pyrazole-8-carboxamide; 35)
3-(8-ethyl-8-azabicyclo[3.2.1]octan-3-yl)-6-fluoro-4H-benzo[4,5]imidazo[1-
,2-b]pyrazole-8-carboxamide; 36)
6-fluoro-3-(4-hydroxypyrrolidin-2-yl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole-
-8-carboxamide; 37)
3-cyano-6-fluoro-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide;
38) 3-cyano-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide; 39)
3-(aminomethyl)-6-fluoro-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamid-
e; 40)
3-(cyclopropanecarboxamidomethylene)-6-fluoro-4H-benzo[4,5]imidazo[-
1,2-b]pyrazole-8-carboxamide; 41)
6-fluoro-3-(4-fluorophenyl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxa-
mide; 42)
6-fluoro-3-(2-fluoro-4-((methylamino)methylene)phenyl)-4H-benzo[-
4,5]imidazo[1,2-b]pyrazole-8-carboxamide; 43)
6-fluoro-3-(4-((methylamino)methyl)phenyl)-4H-benzo[4,5]imidazo[1,2-b]pyr-
azole-8-carboxamide; 44)
6-fluoro-3-(2-fluoro-5-((methylamino)methyl)phenyl)-4H-benzo[4,5]imidazo[-
1,2-b]pyrazole-8-carboxamide; 45)
6-fluoro-3-(pyridin-4-yl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxami-
de; 46)
6-fluoro-3-(4-(piperidin-3-yl)phenyl)-4H-benzo[4,5]imidazo[1,2-b]p-
yrazole-8-carboxamide; 47)
6-fluoro-3-(tetrahydro-2H-pyran-4-yl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole-
-8-carboxamide; 48)
3-(4-(dimethylamino)cyclohexyl)-6-fluoro-4H-benzo[4,5]imidazo[1,2-b]pyraz-
ole-8-carboxamide; 49)
6-fluoro-3-(4-methylpiperazine-1-carbonyl)-4H-benzo[4,5]imidazo[1,2-b]pyr-
azole-8-carboxamide; 50)
3-(1-(cyclopropylmethyl)piperidin-4-yl)-4,4,6-trifluoro-4H-pyrazolo[1,5-.-
alpha.]indole-8-carboxamide; 51)
3-(1-ethylpiperidin-4-yl)-6-fluoro-4-hydroxy-4H-pyrazolo[1,5-.alpha.]indo-
le-8-carboxamide; 52)
3-(1-ethylpiperidin-4-yl)-6-fluoro-4-methyl-4H-benzo[4,5]imidazo[1,2-b]py-
razole-8-carboxamide; 53)
6-fluoro-3-(4-methylpiperidin-4-yl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-
-carboxamide; 54)
3-(1-ethyl-4-methylpiperidin-4-yl)-6-fluoro-4H-benzo[4,5]imidazo[1,2-b]py-
razole-8-carboxamide; 55)
3-(1-cyclopropyl-4-methylpiperidin-4-yl)-6-fluoro-4H-benzo[4,5]imidazo[1,-
2-b]pyrazole-8-carboxamide; 56)
6-fluoro-3-(1-(2-hydroxy-2-methylpropyl)-4-methylpiperidin-4-yl)-4H-benzo-
[4,5]imidazo[1,2-b]pyrazole-8-carboxamide; 57)
3-(1-(cyclopropylmethylene)-4-methylpiperidin-4-yl)-6-fluoro-4H-benzo[4,5-
]imidazo[1,2-b]pyrazole-8-carboxamide; 58)
3-(1-(4,4-difluorocyclohexyl)-4-methylpiperidin-4-yl)-6-fluoro-4H-benzo[4-
,5]imidazo[1,2-b]pyrazole-8-carboxamide; 59)
6-fluoro-3-(4-methyl-1-(tetrahydro-2H-pyran-4-yl)piperidin-4-yl)-4H-benzo-
[4,5]imidazo[1,2-b]pyrazole-8-carboxamide; 60)
6-fluoro-3-(1-(2-fluoroethyl)-4-methylpiperidin-4-yl)-4H-benzo[4,5]imidaz-
o[1,2-b]pyrazole-8-carboxamide; 61)
6-fluoro-3-(4-methyl-1-(2,2,2-trifluoroethyl)piperidin-4-yl)-4H-benzo[4,5-
]imidazo[1,2-b]pyrazole-8-carboxamide; 62)
6-fluoro-3-(4-methyl-1-(3,3,3-trifluoropropyl)piperidin-4-yl)-4H-benzo[4,-
5]imidazo[1,2-b]pyrazole-8-carboxamide; 63)
3-(1-((1-cyanocyclopropyl)methyl)-4-methylpiperidin-4-yl)-6-fluoro-4H-ben-
zo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide; 64)
3-(1-((1-cyanocyclobutyl)methyl)-4-methylpiperidin-4-yl)-6-fluoro-4H-benz-
o[4,5]imidazo[1,2-b]pyrazole-8-carboxamide; 65)
6-fluoro-3-(4-methyl-1-(2-(methylsulfonyl)ethyl)piperidin-4-yl)-4H-benzo[-
4,5]imidazo[1,2-b]pyrazole-8-carboxamide; 66)
6-fluoro-3-(4-methyl-1-((tetrahydro-2H-pyran-4-yl)methyl)piperidin-4-yl)--
4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide; 67)
3-(1-((1-aminocyclopropyl)methyl)-4-methylpiperidin-4-yl)-6-fluoro-4H-ben-
zo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide; 68)
6-fluoro-3-(4-methyl-1-(oxetan-3-ylmethyl)piperidin-4-yl)-4H-benzo[4,5]im-
idazo[1,2-b]pyrazole-8-carboxamide; 69)
6-fluoro-3-(1-(2-methoxyethyl)-4-methylpiperidin-4-yl)-4H-benzo[4,5]imida-
zo[1,2-b]pyrazole-8-carboxamide; 70)
6-fluoro-3-(1-((1-hydroxycyclopropyl)methyl)-4-methylpiperidin-4-yl)-4H-b-
enzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide; 71)
6-fluoro-3-(4-methyl-1-((3-methyloxetan-3-yl)methyl)piperidin-4-yl)-4H-be-
nzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide; 72)
6-fluoro-3-(1-(3-methoxypropyl)-4-methylpiperidin-4-yl)-4H-benzo[4,5]imid-
azo[1,2-b]pyrazole-8-carboxamide; 73)
6-fluoro-3-(4-methyl-1-((1-(methylsulfonyl)cyclopropyl)methyl)piperidin-4-
-yl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide; 74)
6-fluoro-3-(4-methyl-1-(thiazol-2-ylmethyl)piperidin-4-yl)-4H-benzo[4,5]i-
midazo[1,2-b]pyrazole-8-carboxamide; 75)
6-fluoro-3-(4-methyl-1-(methylsulfonyl)piperidin-4-yl)-4H-benzo[4,5]imida-
zo[1,2-b]pyrazole-8-carboxamide; 76)
6-fluoro-3-(1-(3-fluorocyclobutyl)-4-methylpiperidin-4-yl)-4H-benzo[4,5]i-
midazo[1,2-b]pyrazole-8-carboxamide; 77)
6-fluoro-3-(4-methyl-1-(thiophen-2-ylmethyl)piperidin-4-yl)-4H-benzo[4,5]-
imidazo[1,2-b]pyrazole-8-carboxamide; 78)
3-(1-((1-ethylpiperidin-4-yl)methyl)-4-methylpiperidin-4-yl)-6-fluoro-4H--
benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide; 79)
6-fluoro-3-(4-methyl-1-((1-methylazetidin-3-yl)methyl)piperidin-4-yl)-4H--
benzo[4,5]imidazo[1, 2-b]pyrazole-8-carboxamide; 80) ethyl
2-((4-(8-carbamoyl-6-fluoro-4H-benzo[4,5]imidazo[1,2-b]pyrazol-3-yl)-4-me-
thylpiperidin-1-yl)methyl)cyclopropanecarboxylate; 81)
3-(1-((2-(dimethylcarbamoyl)cyclopropyl)methyl)-4-methylpiperidin-4-yl)-6-
-fluoro-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide; 82)
6-fluoro-3-(1-isobutyl-4-methylpiperidin-4-yl)-4H-benzo[4,5]imidazo[1,2-b-
]pyrazole-8-carboxamide; 83)
6-fluoro-3-(4-methyl-1-((4-methylthiazol-5-yl)methyl)piperidin-4-yl)-4H-b-
enzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide; 84)
6-fluoro-3-(4-methyl-1-((1-methyl-1H-imidazol-2-yl)methyl)piperidin-4-yl)-
-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide; 85)
3-(1-((1,2-dimethyl-1H-imidazol-5-yl)methyl)-4-methylpiperidin-4-yl)-6-fl-
uoro-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide 86)
3-(1'-ethyl-4-methyl-[1,4'-bipiperidin]-4-yl)-6-fluoro-4H-benzo[4,5]imida-
zo[1,2-b]pyrazole-8-carboxamide; 87)
6-fluoro-3-(4-methyl-1-((6-oxo-1,6-dihydropyridazin-3-yl)methyl)piperidin-
-4-yl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide; 88)
3-(1-(2-cyanoethyl)-4-methylpiperidin-4-yl)-6-fluoro-4H-benzo[4,5]imidazo-
[1,2-b]pyrazole-8-carboxamide; 89)
6-chloro-3-(1-ethyl-4-methylpiperidin-4-yl)-4H-benzo[4,5]imidazo[1,2-b]py-
razole-8-carboxamide; 90)
3-(1-ethyl-3-methylpyrrolidin-3-yl)-6-fluoro-4H-benzo[4,5]imidazo[1,2-b]p-
yrazole-8-carboxamide; 91)
3-(1,3-dimethylpyrrolidin-3-yl)-6-fluoro-4H-benzo[4,5]imidazo[1,2-b]pyraz-
ole-8-carboxamide; 92)
6-fluoro-3-(1-isopropyl-3-methylpyrrolidin-3-yl)-4H-benzo[4,5]imidazo[1,2-
-b]pyrazole-8-carboxamide; 93)
3-(1-(cyclopropylmethyl)-3-methylpyrrolidin-3-yl)-6-fluoro-4H-benzo[4,5]i-
midazo[1,2-b]pyrazole-8-carboxamide; 94)
6-fluoro-3-(3-methyl-1-(oxetan-3-yl)pyrrolidin-3-yl)-4H-benzo[4,5]imidazo-
[1,2-b]pyrazole-8-carboxamide; 95)
6-fluoro-3-(1-(2-fluoroethyl)-3-methylpyrrolidin-3-yl)-4H-benzo[4,5]imida-
zo[1,2-b]pyrazole-8-carboxamide; 96)
3-(1-((2,2-difluorocyclopropyl)methyl)-3-methylpyrrolidin-3-yl)-6-fluoro--
4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide; 97)
6-fluoro-3-(3-methyl-1-(2,2,2-trifluoroethyl)pyrrolidin-3-yl)-4H-benzo[4,-
5]imidazo[1,2-b]pyrazole-8-carboxamide; 98)
6-fluoro-3-(3-methyl-1-(2-(methylsulfonyl)ethyl)pyrrolidin-3-yl)-4H-benzo-
[4,5]imidazo[1,2-b]pyrazole-8-carboxamide; 99)
6-fluoro-3-(3-methyl-1-(3,3,3-trifluoropropyl)pyrrolidin-3-yl)-4H-benzo[4-
,5]imidazo[1,2-b]pyrazole-8-carboxamide; 100)
3-(1-((1-aminocyclopropyl)methyl)-3-methylpyrrolidin-3-yl)-6-fluoro-4H-be-
nzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide; 101)
3-(1-((1-cyanocyclobutyl)methyl)-3-methylpyrrolidin-3-yl)-6-fluoro-4H-ben-
zo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide; 102)
3-(1-((1-cyanocyclopropyl)methyl)-3-methylpyrrolidin-3-yl)-6-fluoro-4H-be-
nzo[4,5]imidazo[1, 2-b]pyrazole-8-carboxamide; 103)
3-(1-(2-cyanoethyl)-3-methylpyrrolidin-3-yl)-6-fluoro-4H-benzo[4,5]imidaz-
o[1,2-b]pyrazole-8-carboxamide; 104)
3-(1-(cyclopropylmethyl)-3-methylazetidin-3-yl)-6-fluoro-4H-benzo[4,5]imi-
dazo[1,2-b]pyrazole-8-carboxamide; 105)
6-fluoro-3-(1-isopropyl-4-methylpiperidin-4-yl)-4H-benzo[4,5]imidazo[1,2--
b]pyrazole-8-carboxamide; 106)
6-fluoro-3-(4-methyl-1,1-dioxido-2H-thiopyran-4-yl)-4H-benzo[4,5]imidazo[-
1,2-b]pyrazole-8-carboxamide; 107)
3-(1,4-diethylpiperidin-4-yl)-6-fluoro-4H-benzo[4,5]imidazo[1,2-b]pyrazol-
e-8-carboxamide; 108)
3-(4-cyano-1-(cyclopropylmethyl)piperidin-4-yl)-6-fluoro-4H-benzo[4,5]imi-
dazo[1,2-b]pyrazole-8-carboxamide; 109)
3-(1-(cyclopropylmethyl)-4-(hydroxymethyl)piperidin-4-yl)-6-fluoro-4H-ben-
zo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide; 110) Methyl
4-(8-carbamoyl-6-fluoro-4H-benzo[4,5]imidazo[1,2-b]pyrazol-3-yl)-1-(cyclo-
propylmethyl)piperidine-4-carboxylate; 111)
3-(1-(cyclopropylmethyl)-4-methylpiperidin-4-yl)-6-fluoro-2-methyl-4H-ben-
zo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide; 112)
3-(1-ethyl-4-methylpiperidin-4-yl)-6-fluoro-2-methyl-4H-benzo[4,5]imidazo-
[1,2-b]pyrazole-8-carboxamide; 113)
6-fluoro-3-(1-isobutyl-4-methylpiperidin-4-yl)-2-methyl-4H-benzo[4,5]imid-
azo[1,2-b]pyrazole-8-carboxamide; 114)
6-fluoro-3-(1-isopropyl-4-methylpiperidin-4-yl)-2-methyl-4H-benzo[4,5]imi-
dazo[1,2-b]pyrazole-8-carboxamide; 115)
3-(1,4-dimethylpiperidin-4-yl)-6-fluoro-2-methyl-4H-benzo[4,5]imidazo[1,2-
-b]pyrazole-8-carboxamide; 116)
6-fluoro-3-(1-(2-hydroxy-2-methylpropyl)-4-methylpiperidin-4-yl)-2-methyl-
-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide; 117)
3-(1-ethyl-2,4-dimethylpiperidin-4-yl)-6-fluoro-2-methyl-4H-benzo[4,5]imi-
dazo[1,2-b]pyrazole-8-carboxamide; 118)
3-(1-ethyl-3-methylpyrrolidin-3-yl)-6-fluoro-2-methyl-4H-benzo[4,5]imidaz-
o[1,2-b]pyrazole-8-carboxamide; 119)
6-fluoro-3-(1-isopropyl-3-methylpyrrolidin-3-yl)-2-methyl-4H-benzo[4,5]im-
idazo[1,2-b]pyrazole-8-carboxamide; 120)
3-(1-(cyclopropylmethyl)-3-methylpyrrolidin-3-yl)-6-fluoro-2-methyl-4H-be-
nzo[4,5]imidazo[1, 2-b]pyrazole-8-carboxamide; 121)
3-(1,3-dimethylazetidin-3-yl)-6-fluoro-2-methyl-4H-benzo[4,5]imidazo[1,2--
b]pyrazole-8-carboxamide; 122)
3-(1-ethyl-3-methylazetidin-3-yl)-6-fluoro-2-methyl-4H-benzo[4,5]imidazo[-
1,2-b]pyrazole-8-carboxamide; 123)
6-fluoro-3-(1-isopropyl-3-methylazetidin-3-yl)-2-methyl-4H-benzo[4,5]imid-
azo[1,2-b]pyrazole-8-carboxamide; 124)
3-(1-(cyclopropylmethyl)-3-methylazetidin-3-yl)-6-fluoro-2-methyl-4H-benz-
o[4,5]imidazo[1,2-b]pyrazole-8-carboxamide; 125)
6-fluoro-3-(1-(2-hydroxy-2-methylpropyl)-3-methylazetidin-3-yl)-2-methyl--
4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide; 126)
6-fluoro-3-(1-isopropyl-4-methylpiperidin-4-yl)-2-methoxy-4H-benzo[4,5]im-
idazo[1,2-b]pyrazole-8-carboxamide; 127)
2-(benzyloxy)-6-fluoro-3-(1-isopropyl-4-methylpiperidin-4-yl)-4H-benzo[4,-
5]imidazo[1,2-b]pyrazole-8-carboxamide; 128)
6-fluoro-2-(piperidin-4-yl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxa-
mide; and 129)
2-(1-ethylpiperidin-4-yl)-6-fluoro-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8--
carboxamide.
15. The compound of claim 4 or a pharmaceutically acceptable salt
thereof, wherein the R.sub.1 is selected from the group consisting
of H, methyl, methyloxyl, benzyloxyl, ##STR00352## R.sub.3 is
selected from the group consisting of H, F, Cl, Br, CN, and
methyl.
16. The compound of claim 6 or a pharmaceutically acceptable salt
thereof, wherein R.sub.203 is selected from the group consisting of
methyl, ethyl, n-propyl, isopropyl,
--CH.sub.2C(CH.sub.3)(CH.sub.3)(OH), and cyclopropylmethylene,
R.sub.204 is selected from the group consisting of methyl, ethyl,
n-propyl, and isopropyl, R.sub.217-219 are separately and
independently selected from the group consisting of methyl and
ethyl.
17. The compound of claim 8 or a pharmaceutically acceptable salt
thereof, wherein R.sub.207 is selected from the group consisting of
H, methyl, ethyl, n-propyl, isopropyl, --CH.sub.2CF.sub.3,
--CH.sub.2CH.sub.2CF.sub.3, --CH.sub.2CH.sub.2F,
--CH.sub.2CH.sub.2S(.dbd.O).sub.2CH.sub.3, --CH.sub.2CH.sub.2CN,
##STR00353##
18. The compound of claim 9 or a pharmaceutically acceptable salt
thereof, wherein R.sub.208 is selected from the group consisting of
H, methyl, ethyl, n-propyl, isopropyl, cyclopropylmethylene, and
cyclobutyl.
19. The compound of claim 12 or a pharmaceutically acceptable salt
thereof, wherein R.sub.211 is selected from the group consisting of
H, F, Cl, Br, I, CN, OH, NH.sub.2, methyl, ethyl, hydroxylmethyl,
and methyloxylcarbonyl, R.sub.212 is selected from the group
consisting of H, F, Cl, Br, I, CN, OH, NH.sub.2, and methyl,
R.sub.213 is selected from the group consisting of H, F, Cl, Br, I,
CN, OH, and NH.sub.2, R.sub.214 is selected from the group
consisting of H, methyl, ethyl, n-propyl, isopropyl, n-butyl,
isobutyl, tert-butyl, --CH.sub.2CH(OH)(CH.sub.3).sub.2,
--CH.sub.2CH(F)(CH.sub.3).sub.2, --CH.sub.2CH.sub.2F,
--CH.sub.2CF.sub.3, --CH.sub.2CH.sub.2CF.sub.3,
--CH.sub.2CH.sub.2NH.sub.2, --CH.sub.2CH.sub.2OH,
--CH.sub.2CH.sub.2OCH.sub.3, --CH.sub.2CH.sub.2CH.sub.2OCH.sub.3,
--CH.sub.2CH.sub.2N(CH.sub.3).sub.2, --S(.dbd.O).sub.2CH.sub.3,
--CH.sub.2CH.sub.2S(.dbd.O).sub.2CH.sub.3, ##STR00354##
cyclopropyl, cyclopropylmethylene, ##STR00355##
20. The compound of claim 12 or a pharmaceutically acceptable salt
thereof, wherein R.sub.2 is selected from the group consisting of
##STR00356## ##STR00357## ##STR00358## ##STR00359##
##STR00360##
21. The compound of claim 7 or a pharmaceutically acceptable salt
thereof, wherein R.sub.2 is selected from the group consisting of
##STR00361##
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
This application is a National Stage of International Application
No. PCT/CN2015/075363, filed on Mar. 30, 2015 and published in
Chinese as WO 2015/154630 on Oct. 15, 2015. This application claims
the priority to Chinese Application No. 201410144173.0, filed on
Apr. 10, 2014 and Chinese Application No. 201510113090.X, filed on
Mar. 13, 2015. The entire disclosures of the above applications are
incorporated herein by reference.
FIELD OF THE INVENTION
This invention relates to a series of analogs of
4H-Pyrazolo[1,5-.alpha.]benzimidazole compounds as PARP inhibitors.
To be specific, this invention relates to the compounds of formula
(I) or pharmaceutically acceptable salts thereof as PARP
inhibitors.
BACKGROUND OF THE INVENTION
PARP is a family of enzymes that catalyzes the addition of an
ADP-ribose residue to various target proteins. To date, as many as
18 isoforms have been identified and characterized. Despite the
large number of enzymes in the family, PARP-1 is responsible for
more than 90% of the ADP-ribosylation within cells.
PARP-1 has long been associated with DNA repair and maintenance of
genomic function. Following DNA damage, PARP-1 becomes instantly
activated by binding to DNA breaks. After the structural changes,
it begins to utilize NAD+ to synthesize poly(ADP) ribose as a
signal for the other repairing enzymes (such as DNA ligase III, DNA
polymerase beta). This process of PARP-1 binding and activation
(known as base excision repair) helps amplify the repair process in
which single-strand DNA breaks (SSB) are targeted. SSB are
generally initiated by oxidative damages that are caused by cell's
own metabolic processes as well as by exogenous chemotherapeutical
agents and radiation. It is well-known that many types of
anti-cancer therapies, such as DNA alkylating agents,
platinum-based drugs, topoisomerase inhibitors and radiotherapy,
are concomitant with DNA damages. These therapies are shadowed by
the emergence of drug resistance, particularly in PARP-1 dominated
DNA repair pathway. Recent studies have confirmed that selective
PARP-1 inhibitors greatly enhance the antitumor efficacies of TMZ
and cisplatin.
BRCA1 and BRCA2 play an essential role in homologous recombination
(HR). DNA breaks arising during DNA replication can only be
repaired by HR. In 2005, Bryant and Farmer (Nature, 2005, 913 and
917) independently discovered that cell lines deficient in BACA1
and BACA2 were very sensitive to PARP-1 inhibitors, resulting in
cells death. Breast cancer genes BRCA1/2 have long been
characterized as tumor suppressor genes that play an indispensable
role in the repair of DNA double strand breaks. BRCA1/2 mutation
carriers in ovarian cancer and prostate cancer are also at an
elevated risk. Therefore PARP-1 inhibitors could also be used as a
standalone therapy for such types of tumors that are already
deficient in certain types of DNA repair mechanism.
PARP-1 has been an actively pursued oncology target for 30 years
and Ferraris has entirely summarized the progress in this field (J.
Med. Chem. 2010, 4561). A series compounds are in clinical studies
regardless as a single agent or a synergist, such as veliparib
(ABT-888), niraparib (MK-4827), BMN-673, CEP-977, BGP-15, E-7016,
MP-124 and IND-1022. Recently certain heterocyclic compounds have
also been disclosed as being useful in the treatment of a variety
of cancers in some patents, for example, WO2014009872 (A1),
WO2014019468 (A1), WO2014023390 (A2), WO2013182580, WO2013164061
(A1), EP2656843 (A1).
In addition, PARP-1 inhibition has been an actively pursued drug
discovery target in wide ranges of therapeutic areas compassing
stroke, cardiac ischemia, inflammation, and diabetes (Pharmacol.
Rev. 2002, 54, 375.).
Although efforts have always been made to develop PARP-1 inhibitors
for treating cancer and other diseases, satisfactory treatment has
not yet been achieved. Thus, there exists a need for the
development of new PARP-1 inhibitors.
SUMMARY OF THE INVENTION
An objective of the present invention is to provide compounds shown
in formula (I) or pharmaceutically acceptable salts thereof,
##STR00001## wherein,
D is selected from the group consisting of
--C(R.sub.d1)(R.sub.d2)--, --C(.dbd.O)N(R.sub.d3)--,
--N(R.sub.d4)--, --C(.dbd.NR.sub.d5)--,
--S(.dbd.O).sub.2N(R.sub.d6)--, --S(.dbd.O) N(R.sub.d7)--, --O--,
--S--, --C(.dbd.O)O--, --C(.dbd.O)--, --C(.dbd.S)--, --S(.dbd.O)--,
or --S(.dbd.O).sub.2--;
R.sub.1-3, R.sub.d1, and R.sub.d2 are separately and independently
selected from the group consisting of H, F, Cl, Br, I, CN, OH, SH,
and NH.sub.2, or selected from the group, optionally substituted by
R.sub.01, consisting of C.sub.1-10 alkyl, C.sub.1-10 heteroalkyl,
C.sub.3-10 cyclohydrocarbyl, C.sub.3-10 heterocyclohydrocarbyl,
C.sub.1-10 alkyl substituted by C.sub.3-10 cyclohydrocarbyl or
C.sub.3-10 heterocyclohydrocarbyl, and C.sub.1-10 heteroalkyl
substituted by C.sub.3-10 cyclohydrocarbyl or C.sub.3-10
heterocyclohydrocarbyl.
R.sub.01 is selected from the group consisting of F, Cl, Br, I, CN,
OH, SH, NH.sub.2, and R.sub.02;
R.sub.02 is selected from the group consisting of C.sub.1-10 alkyl,
C.sub.1-10 alkylamino, N,N-di(C.sub.1-10 alkyl) amino, C.sub.1-10
alkyloxyl, C.sub.1-10 alkylacyl, C.sub.1-10 alkyloxylcarbonyl,
C.sub.1-10 alkylsulfonyl, C.sub.1-10 alkylsulfinyl, C.sub.3-10
cycloalkyl, C.sub.3-10 cycloalkylamino, C.sub.3-10
heterocycloalkylamino, C.sub.3-10 cycloalkyloxyl, C.sub.3-10
cycloalkylacyl, C.sub.3-10 cycloalkyloxylcarbonyl, C.sub.3-10
cycloalkylsulfonyl, and C.sub.3-10 cycloalkylsulfinyl; the
heteroatom or heteroatomic group is separately and independently
selected from the group consisting of --C(.dbd.O)N(R.sub.d3)--,
--N(R.sub.d4)--, --C(.dbd.NR.sub.d5)--,
--S(.dbd.O).sub.2N(R.sub.d6)--, --S(.dbd.O) N(R.sub.d7)--, --O--,
--S--, --C(.dbd.O)O--, --C(.dbd.O)--, --C(.dbd.S)--, --S(.dbd.O)--,
and --S(.dbd.O).sub.2--;
R.sub.d3-d7 are separately and independently selected from the
group consisting of H, and R.sub.03;
R.sub.03 is selected from the group consisting of C.sub.1-10 alkyl,
C.sub.1-10 alkylacyl, C.sub.1-10 alkyloxylcarbonyl, C.sub.1-10
alkylsulfonyl, C.sub.1-10 alkylsulfinyl, C.sub.3-10 cycloalkyl,
C.sub.3-10 cycloalkylacyl, C.sub.3-10 cycloalkyloxylcarbonyl,
C.sub.3-10 cycloalkylsulfonyl, and C.sub.3-10
cycloalkylsulfinyl;
R.sub.02, and R.sub.03 are optionally substituted by R.sub.001;
R.sub.001 is selected from the group consisting of F, Cl, Br, I,
CN, OH, N(CH.sub.3).sub.2, NH(CH.sub.3), NH.sub.2, CF.sub.3,
(NH.sub.2)CH.sub.2, (HO)CH.sub.2, CH.sub.3, CH.sub.3O, HC(.dbd.O),
CH.sub.3OC(.dbd.O), CH.sub.3S(.dbd.O).sub.2, and CH.sub.3S(.dbd.O);
and
the number of R.sub.01, R.sub.001, heteroatom, or heteroatomic
group is separately and independently selected from 0, 1, 2, or
3.
In an embodiment of this invention, D is selected from --NH--,
--N(CH.sub.3)--, --C(F).sub.2--, --C(H) (F)--, and
--C(H)(OH)--.
In an embodiment of this invention, R.sub.1-3 are separately and
independently selected from the group consisting of H, F, Cl, Br,
I, CN, OH, SH, NH.sub.2, C.sub.1-6 alkyl, C.sub.1-6 alkyloxyl,
benzyloxyl, --CH.sub.2N(R.sub.21)(R.sub.22),
##STR00002## in which,
L and D.sub.21 are separately and independently selected from the
group consisting of --C(R.sub.d1)(R.sub.d2)--,
--C(.dbd.O)N(R.sub.d3)--, --N(R.sub.d4)--, --C(.dbd.NR.sub.d5)--,
--S(.dbd.O).sub.2N(R.sub.d6)--, --S(.dbd.O) N(R.sub.d7)--, --O--,
--S--, --C(.dbd.O)--, --C(.dbd.O)O--, --C(.dbd.S)--, --S(.dbd.O)--,
or --S(.dbd.O).sub.2--;
L may also be a single bond for a linkage purpose only;
T.sub.21-22 are separately and independently selected from the
group consisting of C(R.sub.t) and N;
X is selected from (CH2).sub.n optionally substituted by R.sub.01,
and n is selected from 0, 1, 2, or 3, and preferably 0, 1, or
2;
Y is selected from (CH2).sub.m optionally substituted by R.sub.01,
and m is selected from 0, 1, 2, or 3, and preferably 1, 2, or
3;
R.sub.21-23 and R.sub.d3-d7 are separately and independently
selected from the group consisting of H and R.sub.03;
R.sub.24-27, R.sub.d1, R.sub.d2, and R.sub.t are separately and
independently selected from the group consisting of H, F, Cl, Br,
I, CN, OH, SH, and NH.sub.2, or selected from the group, optionally
substituted by R.sub.01, consisting of C.sub.1-10 alkyl, C.sub.1-10
heteroalkyl, C.sub.3-10 cyclohydrocarbyl, C.sub.3-10
heterocyclohydrocarbyl, C.sub.1-10 alkyl substituted by C.sub.3-10
cyclohydrocarbyl or C.sub.3-10 heterocyclohydrocarbyl, and
C.sub.1-10 heteroalkyl substituted by C.sub.3-10 cyclohydrocarbyl
or C.sub.3-10 heterocyclohydrocarbyl;
R.sub.01 is selected from the group consisting of F, Cl, Br, I, CN,
OH, SH, NH.sub.2, and R.sub.02;
R.sub.02 is selected from the group consisting of C.sub.1-10 alkyl,
C.sub.1-10 alkylamino, N,N-di(C.sub.1-10 alkyl)amino, C.sub.1-10
alkyloxyl, C.sub.1-10 alkylacyl, C.sub.1-10 alkyloxylcarbonyl,
C.sub.1-10 alkylsulfonyl, C.sub.1-10 alkylsulfinyl, C.sub.3-10
cycloalkyl, C.sub.3-10 cycloalkylamino, C.sub.3-10
heterocycloalkylamino, C.sub.3-10 cycloalkyloxyl, C.sub.3-10
cycloalkylacyl, C.sub.3-10 cycloalkyloxylcarbonyl, C.sub.3-10
cycloalkylsulfonyl, and C.sub.3-10 cycloalkylsulfinyl;
the heteroatom or heteroatomic group is separately and
independently selected from the group consisting of
--C(.dbd.O)N(R.sub.d3)--, --N(R.sub.d4)--, --C(.dbd.NR.sub.d5)--,
--S(.dbd.O).sub.2N(R.sub.d6)--, --S(.dbd.O) N(R.sub.d7)--, --O--,
--S--, --C(.dbd.O)O--, --C(.dbd.O)--, --C(.dbd.S)--, --S(.dbd.O)--,
and/or --S(.dbd.O).sub.2--;
R.sub.d3-d7 are separately and independently selected from the
group consisting of H, and R.sub.03;
R.sub.03 is selected from the group consisting of C.sub.1-10 alkyl,
C.sub.1-10 alkylacyl, C.sub.1-10 alkyloxylcarbonyl, C.sub.1-10
alkylsulfonyl, C.sub.1-10 alkylsulfinyl, C.sub.3-10 cycloalkyl,
C.sub.3-10 cycloalkylacyl, C.sub.3-10 cycloalkyloxylcarbonyl,
C.sub.3-10 cycloalkylsulfonyl, and C.sub.3-10
cycloalkylsulfinyl;
R.sub.02, and R.sub.03 are optionally substituted by R.sub.001;
R.sub.001 is selected from the group consisting of F, Cl, Br, I,
CN, OH, N(CH.sub.3).sub.2, NH(CH.sub.3), NH.sub.2, CF.sub.3,
(NH.sub.2)CH.sub.2, (HO)CH.sub.2, CH.sub.3, CH.sub.3O, HC(.dbd.O),
CH.sub.3OC(.dbd.O), CH.sub.3S(.dbd.O).sub.2, and CH.sub.3S(.dbd.O);
and the number of R.sub.01, R.sub.001, heteroatom, or heteroatomic
group is separately and independently selected from 0, 1, 2, or
3.
In an embodiment of this invention, R.sub.1 and R.sub.3 are
separately and independently selected from the group consisting of
H, F, Cl, Br, I, CN, OH, SH, NH.sub.2, C.sub.1-3 alkyl, C.sub.1-3
alkyloxyl, benzyloxyl, and
##STR00003## in which R101 is selected from the group consisting of
H, methyl, ethyl, n-propyl, or isopropyl.
In an embodiment of this invention, R.sub.1 is selected from the
group consisting of H, methyl, methyloxyl, benzyloxyl,
##STR00004##
In an embodiment of this invention, R.sub.3 is selected from the
group consisting of H, F, Cl, Br, CN, and methyl.
In an embodiment of this invention, R.sub.2 is selected from
--CH.sub.2N(R.sub.201)(R.sub.202), in which R.sub.201 and R.sub.202
are separately and independently selected from the group consisting
of H, C.sub.1-3 alkyl, C.sub.1-3 alkylacyl, C.sub.3-6
cycloalkylacyl, or C.sub.3-6cycloalkyl.
In an embodiment of this invention, R.sub.201 and R.sub.202 are
separately and independently selected from the group consisting of
H or cyclopropylacyl.
In an embodiment of this invention, R.sub.2 is selected from the
group consisting of
##STR00005##
In an embodiment of this invention, R.sub.2 is selected from the
group consisting of
##STR00006## in which R.sub.203, R.sub.204, R.sub.217, and
R.sub.218 are separately and independently selected from the group
consisting of H, substituted or unsubstituted C.sub.1-3 alkyl,
cyclopropyl, or cyclopropylmethylene, wherein the substituent is
selected from the group consisting of F, Cl, Br, I, CN, OH,
NH.sub.2, methyl, or methyloxyl, and the number of substituents is
0, 1, 2, or 3.
In an embodiment of this invention, R.sub.203 is selected from the
group consisting of methyl, ethyl, n-propyl, isopropyl,
--CH.sub.2C(CH.sub.3)(CH.sub.3)(OH), and cyclopropylalkylene.
In an embodiment of this invention, R.sub.204 is selected from the
group consisting of methyl, ethyl, n-propyl, and isopropyl.
In an embodiment of this invention, R.sub.217-219 are separately
and independently selected from the group consisting of methyl and
ethyl.
In an embodiment of this invention, R.sub.2 is selected from the
group consisting of
##STR00007##
In an embodiment of this invention, R.sub.2 is selected from
##STR00008## in which R.sub.205 and R.sub.206 are separately and
independently selected from the group consisting of H, substituted
or unsubstituted C.sub.1-3 alkyl, cyclopropyl, or
cyclopropylmethylene, wherein the substituent is selected from the
group consisting of F, Cl, Br, I, CN, OH, NH.sub.2, methyl, or
methyloxyl, and the number of substituents is 0, 1, 2, or 3.
In an embodiment of this invention, R.sub.205 and R.sub.206 are
separately, independently and preferably selected from the group
consisting of H, methyl, ethyl, n-propyl, and isopropyl, and
R.sub.206 is also preferably selected from the group consisting of
F, Cl, Br, I, CN, OH, and NH.sub.2.
In an embodiment of this invention, R.sub.2 is selected from
##STR00009##
In an embodiment of this invention, R.sub.2 is selected from the
group consisting of
##STR00010##
In an embodiment of this invention, R.sub.2 is selected from
##STR00011## in which R.sub.207 is selected from the group
consisting of H, substituted or unsubstituted C.sub.1-3 alkyl,
cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclobutylmethylene,
oxacyclobutyl or oxacyclobutylalkylene, wherein the substituent is
selected from the group consisting of F, Cl, Br, I, CN, OH,
NH.sub.2, methyl, CF.sub.3, methyloxyl, and methylsulfonyl, and the
number of substituents is 0, 1, 2, or 3.
In an embodiment of this invention, R.sub.207 is selected from the
group consisting of H, methyl, ethyl, n-propyl, isopropyl,
--CH.sub.2CF.sub.3, --CH.sub.2CH.sub.2CF.sub.3,
--CH.sub.2CH.sub.2F, --CH.sub.2CH.sub.2S(.dbd.O).sub.2CH.sub.3,
--CH.sub.2CH.sub.2CN,
##STR00012##
In an embodiment of this invention, R.sub.2 is selected from the
group consisting of
##STR00013##
In an embodiment of this invention, R.sub.2 is selected from the
group consisting of
##STR00014## in which R.sub.208 is selected from the group
consisting of H, substituted or unsubstituted C.sub.1-4 alkyl,
wherein the substituent is selected from the group consisting of F,
Cl, Br, I, CN, OH, NH.sub.2, methyl, CF.sub.3, methyloxyl, and
methylsulfonyl, and the number of substituents is 0, 1, 2, or
3.
In an embodiment of this invention, R.sub.208 is selected from the
group consisting of H, methyl, ethyl, n-propyl, isopropyl,
cyclopropylmethylene, and cyclobutyl.
In an embodiment of this invention, R.sub.2 is selected from the
group consisting of
##STR00015##
In an embodiment of this invention, R.sub.2 is selected from
##STR00016## in which R.sub.209 is selected from the group
consisting of --C(R.sub.d1)(R.sub.d2)--, --C(.dbd.O)N(R.sub.d3)--,
--N(R.sub.d4)--, --C(.dbd.NR.sub.d5)--,
--S(.dbd.O).sub.2N(R.sub.d6)--, --S(.dbd.O) N(R.sub.d7)--, --O--,
--S--, --C(.dbd.O)O--, --C(.dbd.O)--, --C(.dbd.S)--, --S(.dbd.O)--,
or --S(.dbd.O).sub.2--, wherein R.sub.d1-d7 are as defined in claim
1.
In an embodiment of this invention, R.sub.209 is selected from the
group consisting of O and S(.dbd.O).sub.2.
In an embodiment of this invention, R.sub.2 is selected from
##STR00017## in which R.sub.210 is selected from the group
consisting of H, F, Cl, Br, I, CN, OH, SH, NH.sub.2,
N,N-di(C.sub.1-3 alkyl)amino, and C.sub.1-3 alkylamino.
In an embodiment of this invention, R.sub.210 is selected from the
group consisting of dimethylamino, methylamino, H, F, Cl, Br, I,
CN, OH, and NH.sub.2.
In an embodiment of this invention, R.sub.2 is selected from
##STR00018## in which R.sub.211-214 are selected from the group
consisting of H, or substituted or unsubstituted C.sub.1-4
alkyloxylcarbonyl, C.sub.1-4 alkyl, 3-6 membered cycloalkyl, 3-6
membered cycloalkylmethylene, or unsaturated 5-6 membered
heterocyclohydrocarbyl, wherein the substitutent includes
R.sub.215, and R.sub.211-213 are also selected from the group
consisting of H, F, Cl, Br, I, CN, OH, and NH.sub.2, in which the
cycloalkyl or unsaturated heterocyclohydrocarbyl has O, S or
NR.sub.216 with a number of 0, 1 or 2 wherein
R.sub.216 is selected from the group consisting of H and
C.sub.1-4alkyl substituted by R.sub.215,
R.sub.215 is selected from the group consisting of F, Cl, Br, I,
CN, OH, NH.sub.2, methyl, ethyl, methyloxyl, ethyloxyl, formyl,
acetyl, methylsulfonyl, ethylsulfonyl, methyloxylcarbonyl,
ethyloxylcarbonyl, dimethylamino, diethylamino,
dimethylaminocarbonyl, diethylaminocarbonyl, oxo,
the number of R.sub.215 is 1, 1, 2, or 3,
optionally, R.sub.212 and R.sub.213 may join together to form a
linker selected from the group consisting of --CH.sub.2--,
--CH.sub.2CH.sub.2--, or --CH.sub.2CH.sub.2CH.sub.2--;
In an embodiment of this invention,
R.sub.211 is selected from the group consisting of H, F, Cl, Br, I,
CN, OH, NH.sub.2, methyl, ethyl, hydroxylmethyl, and
methyloxylcarbonyl,
R.sub.212 is selected from the group consisting of H, F, Cl, Br, I,
CN, OH, NH.sub.2, and methyl,
R.sub.213 is selected from the group consisting of H, F, Cl, Br, I,
CN, OH, and NH.sub.2,
R.sub.214 is selected from the group consisting of H, methyl,
ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl,
--CH.sub.2C(OH)(CH.sub.3).sub.2, --CH.sub.2C(F)(CH.sub.3).sub.2,
--CH.sub.2CH.sub.2F, --CH.sub.2CF.sub.3,
--CH.sub.2CH.sub.2CF.sub.3, --CH.sub.2CH.sub.2NH.sub.2,
--CH.sub.2CH.sub.2OH, --CH.sub.2CH.sub.2CN,
--CH.sub.2CH.sub.2OCH.sub.3, --CH.sub.2CH.sub.2CH.sub.2OCH.sub.3,
--CH.sub.2CH.sub.2N(CH.sub.3).sub.2, --S(.dbd.O).sub.2CH.sub.3,
--CH.sub.2CH.sub.2S(.dbd.O).sub.2CH.sub.3,
##STR00019## cyclopropyl, cyclopropylmethylene,
##STR00020## ##STR00021##
In an embodiment of this invention, R.sub.2 is selected from the
group consisting of
##STR00022## ##STR00023## ##STR00024## ##STR00025## ##STR00026##
##STR00027##
In an embodiment of this invention, R.sub.2 is selected from
##STR00028## in which T.sub.22 is selected from the group
consisting of N or C(R.sub.224), and R.sub.220-224 are separately
and independently selected from the group consisting of H, F, Cl,
Br, I, CN, OH, SH, NH.sub.2, C.sub.1-3 alkylamino-C.sub.1-3 alkyl,
and
##STR00029##
In an embodiment of this invention, the C.sub.1-3
alkylamino-C.sub.1-3 alkyl is selected from
methylaminomethylene.
In an embodiment of this invention,
R.sub.2 is selected from the group consisting of
##STR00030##
In an embodiment of this invention, the compounds or
pharmaceutically acceptable salts thereof are selected from: 1)
6-fluoro-3-(piperidin-4-yl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxa-
mide; 2)
3-(1-ethylpiperidin-4-yl)-6-fluoro-4H-benzo[4,5]imidazo[1,2-b]pyr-
azole-8-carboxamide; 3)
6-fluoro-3-(1-(2-fluoroethyl)piperidin-4-yl)-4H-benzo[4,5]imidazo[1,2-b]p-
yrazole-8-carboxamide; 4)
3-(1-cyclopropylpiperidin-4-yl)-6-fluoro-4H-benzo[4,5]imidazo[1,2-b]pyraz-
ole-8-carboxamide; 5)
3-(1-(cyclopropylmethyl)piperidin-4-yl)-6-fluoro-4H-benzo[4,5]imidazo[1,2-
-b]pyrazole-8-carboxamide; 6)
6-fluoro-3-(1-(2-hydroxy-2-methylpropyl)piperidin-4-yl)-4H-benzo[4,5]imid-
azo[1,2-b]pyrazole-8-carboxamide; 7)
6-fluoro-3-(1-(2-fluoro-2-methylpropyl)piperidin-4-yl)-4H-benzo[4,5]imida-
zo[1,2-b]pyrazole-8-carboxamide; 8)
3-(1-(cyclopropanecarbonyl)piperidin-4-yl)-6-fluoro-4H-benzo[4,5]imidazo[-
1,2-b]pyrazole-8-carboxamide; 9)
6-fluoro-3-(1-methylpiperidin-4-yl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-
-carboxamide; 10)
6-fluoro-3-(1-isopropylpiperidin-4-yl)-4H-benzo[4,5]imidazo[1,2-b]pyrazol-
e-8-carboxamide; 11)
6-fluoro-3-(1-(oxetan-3-yl)piperidin-4-yl)-4H-benzo[4,5]imidazo[1,2-b]pyr-
azole-8-carboxamide; 12)
6-fluoro-3-(1-propylpiperidin-4-yl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-
-carboxamide; 13)
3-(1-(2-aminoethyl)piperidin-4-yl)-6-fluoro-4H-benzo[4,5]imidazo[1,2-b]py-
razole-8-carboxamide; 14)
3-(1-(2-(dimethylamino)ethyl)piperidin-4-yl)-6-fluoro-4H-benzo[4,5]imidaz-
o[1,2-b]pyrazole-8-carboxamide; 15)
6-fluoro-3-(1-(2-methoxyethyl)piperidin-4-yl)-4H-benzo[4,5]imidazo[1,2-b]-
pyrazole-8-carboxamide 16)
6-fluoro-3-(1-(2-hydroxyethyl)piperidin-4-yl)-4H-benzo[4,5]imidazo[1,2-b]-
pyrazole-8-carboxamide; 17)
3-(1-ethylpiperidin-3-yl)-6-fluoro-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8--
carboxamide; 18)
3-(1-ethylazepan-4-yl)-6-fluoro-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-car-
boxamide; 19)
6-fluoro-3-(1-methylazepan-4-yl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-ca-
rboxamide; 20)
6-fluoro-3-(1-methylpyrrolidin-3-yl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole--
8-carboxamide; 21)
3-(1-ethylpyrrolidin-3-yl)-6-fluoro-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-
-carboxamide; 22)
6-fluoro-3-(1-isopropylpyrrolidin-3-yl)-4H-benzo[4,5]imidazo[1,2-b]pyrazo-
le-8-carboxamide; 23)
6-fluoro-3-(pyrrolidin-2-yl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carbox-
amide; 24)
6-fluoro-3-(1-propylpyrrolidin-2-yl)-4H-benzo[4,5]imidazo[1,2-b-
]pyrazole-8-carboxamide;
6-fluoro-3-(1-methylpyrrolidin-2-yl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole--
8-carboxamide; 25)
3-(1-ethylpyrrolidin-2-yl)-6-fluoro-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-
-carboxamide; 26)
3-(1-ethylpiperidin-4-yl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxami-
de; 27)
6-fluoro-3-(1-propylpyrrolidin-2-yl)-4H-benzo[4,5]imidazol[1,2-b]p-
yrazole-8-carboxamide; 28)
6-fluoro-3-(3-methyl-3-azabicyclo[3.1.0]hexan-1-yl)-4H-benzo[4,5]imidazo[-
1,2-b]pyrazole-8-carboxamide; 29)
3-(3-ethyl-3-azabicyclo[3.1.0]hexan-1-yl)-6-fluoro-4H-benzo[4,5]imidazo[1-
,2-b]pyrazole-8-carboxamide; 30)
3-(3-cyclobutyl-3-azabicyclo[3.1.0]hexan-1-yl)-6-fluoro-4H-benzo[4,5]imid-
azo[1,2-b]pyrazole-8-carboxamide; 31)
3-(3-(cyclopropylmethylene)-3-azabicyclo[3.1.0]hexan-1-yl)-6-fluoro-4H-be-
nzo[4,5]imidazo[1, 2-b]pyrazole-8-carboxamide; 32)
6-fluoro-3-(3-isopropyl-3-azabicyclo[3.1.0]hexan-1-yl)-4H-benzo[4,5]imida-
zo[1,2-b]pyrazole-8-carboxamide; 33)
3-(3-azabicyclo[3.1.0]hexan-6-yl)-6-fluoro-4H-benzo[4,5]imidazo[1,2-b]pyr-
azole-8-carboxamide; 34)
3-(3-ethyl-3-azabicyclo[3.1.0]hexan-6-yl)-6-fluoro-4H-benzo[4,5]imidazo[1-
,2-b]pyrazole-8-carboxamide; 35)
3-(8-ethyl-8-azabicyclo[3.2.1]octan-3-yl)-6-fluoro-4H-benzo[4,5]imidazo[1-
,2-b]pyrazole-8-carboxamide; 36)
6-fluoro-3-(4-hydroxypyrrolidin-2-yl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole-
-8-carboxamide; 37)
3-cyano-6-fluoro-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide;
38) 3-cyano-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide; 39)
3-(aminomethyl)-6-fluoro-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamid-
e; 40)
3-(cyclopropanecarboxamidomethylene)-6-fluoro-4H-benzo[4,5]imidazo[-
1,2-b]pyrazole-8-carboxamide; 41)
6-fluoro-3-(4-fluorophenyl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxa-
mide; 42)
6-fluoro-3-(2-fluoro-4-((methylamino)methylene)phenyl)-4H-benzo[-
4,5]imidazo[1,2-b]pyrazole-8-carboxamide; 43)
6-fluoro-3-(4-((methylamino)methyl)phenyl)-4H-benzo[4,5]imidazo[1,2-b]pyr-
azole-8-carboxamide; 44)
6-fluoro-3-(2-fluoro-5-((methylamino)methyl)phenyl)-4H-benzo[4,5]imidazo[-
1,2-b]pyrazole-8-carboxamide; 45)
6-fluoro-3-(pyridin-4-yl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxami-
de; 46)
6-fluoro-3-(4-(piperidin-3-yl)phenyl)-4H-benzo[4,5]imidazo[1,2-b]p-
yrazole-8-carboxamide; 47)
6-fluoro-3-(tetrahydro-2H-pyran-4-yl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole-
-8-carboxamide; 48)
3-(4-(dimethylamino)cyclohexyl)-6-fluoro-4H-benzo[4,5]imidazo[1,2-b]pyraz-
ole-8-carboxamide; 49)
6-fluoro-3-(4-methylpiperazine-1-carbonyl)-4H-benzo[4,5]imidazo[1,2-b]pyr-
azole-8-carboxamide; 50)
3-(1-(cyclopropylmethyl)piperidin-4-yl)-4,4,6-trifluoro-4H-pyrazolo[1,5-.-
alpha.]indole-8-carboxamide; 51)
3-(1-ethylpiperidin-4-yl)-6-fluoro-4-hydroxy-4H-pyrazolo[1,5-.alpha.]indo-
le-8-carboxamide; 52)
3-(1-ethylpiperidin-4-yl)-6-fluoro-4-methyl-4H-benzo[4,5]imidazo[1,2-b]py-
razole-8-carboxamide; 53)
6-fluoro-3-(4-methylpiperidin-4-yl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-
-carboxamide; 54)
3-(1-ethyl-4-methylpiperidin-4-yl)-6-fluoro-4H-benzo[4,5]imidazo[1,2-b]py-
razole-8-carboxamide; 55)
3-(1-cyclopropyl-4-methylpiperidin-4-yl)-6-fluoro-4H-benzo[4,5]imidazo[1,-
2-b]pyrazole-8-carboxamide; 56)
6-fluoro-3-(1-(2-hydroxy-2-methylpropyl)-4-methylpiperidin-4-yl)-4H-benzo-
[4,5]imidazo[1,2-b]pyrazole-8-carboxamide; 57)
3-(1-(cyclopropylmethylene)-4-methylpiperidin-4-yl)-6-fluoro-4H-benzo[4,5-
]imidazo[1,2-b]pyrazole-8-carboxamide; 58)
3-(1-(4,4-difluorocyclohexyl)-4-methylpiperidin-4-yl)-6-fluoro-4H-benzo[4-
,5]imidazo[1,2-b]pyrazole-8-carboxamide; 59)
6-fluoro-3-(4-methyl-1-(tetrahydro-2H-pyran-4-yl)piperidin-4-yl)-4H-benzo-
[4,5]imidazo[1,2-b]pyrazole-8-carboxamide; 60)
6-fluoro-3-(1-(2-fluoroethyl)-4-methylpiperidin-4-yl)-4H-benzo[4,5]imidaz-
o[1,2-b]pyrazole-8-carboxamide; 61)
6-fluoro-3-(4-methyl-1-(2,2,2-trifluoroethyl)piperidin-4-yl)-4H-benzo[4,5-
]imidazo[1,2-b]pyrazole-8-carboxamide; 62)
6-fluoro-3-(4-methyl-1-(3,3,3-trifluoropropyl)piperidin-4-yl)-4H-benzo[4,-
5]imidazo[1,2-b]pyrazole-8-carboxamide; 63)
3-(1-((1-cyanocyclopropyl)methyl)-4-methylpiperidin-4-yl)-6-fluoro-4H-ben-
zo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide; 64)
3-(1-((1-cyanocyclobutyl)methyl)-4-methylpiperidin-4-yl)-6-fluoro-4H-benz-
o[4,5]imidazo[1,2-b]pyrazole-8-carboxamide; 65)
6-fluoro-3-(4-methyl-1-(2-(methylsulfonyl)ethyl)piperidin-4-yl)-4H-benzo[-
4,5]imidazo[1,2-b]pyrazole-8-carboxamide; 66)
6-fluoro-3-(4-methyl-1-((tetrahydro-2H-pyran-4-yl)methyl)piperidin-4-yl)--
4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide; 67)
3-(1-((1-aminocyclopropyl)methyl)-4-methylpiperidin-4-yl)-6-fluoro-4H-ben-
zo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide; 68)
6-fluoro-3-(4-methyl-1-(oxetan-3-ylmethyl)piperidin-4-yl)-4H-benzo[4,5]im-
idazo[1,2-b]pyrazole-8-carboxamide; 69)
6-fluoro-3-(1-(2-methoxyethyl)-4-methylpiperidin-4-yl)-4H-benzo[4,5]imida-
zo[1,2-b]pyrazole-8-carboxamide; 70)
6-fluoro-3-(1-((1-hydroxycyclopropyl)methyl)-4-methylpiperidin-4-yl)-4H-b-
enzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide; 71)
6-fluoro-3-(4-methyl-1-((3-methyloxetan-3-yl)methyl)piperidin-4-yl)-4H-be-
nzo[4,5]imidazo[1, 2-b]pyrazole-8-carboxamide; 72)
6-fluoro-3-(1-(3-methoxypropyl)-4-methylpiperidin-4-yl)-4H-benzo[4,5]imid-
azo[1,2-b]pyrazole-8-carboxamide; 73)
6-fluoro-3-(4-methyl-1-((1-(methylsulfonyl)cyclopropyl)methyl)piperidin-4-
-yl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide; 74)
6-fluoro-3-(4-methyl-1-(thiazol-2-ylmethyl)piperidin-4-yl)-4H-benzo[4,5]i-
midazo[1,2-b]pyrazole-8-carboxamide; 75)
6-fluoro-3-(4-methyl-1-(methylsulfonyl)piperidin-4-yl)-4H-benzo[4,5]imida-
zo[1,2-b]pyrazole-8-carboxamide; 76)
6-fluoro-3-(1-(3-fluorocyclobutyl)-4-methylpiperidin-4-yl)-4H-benzo[4,5]i-
midazo[1,2-b]pyrazole-8-carboxamide; 77)
6-fluoro-3-(4-methyl-1-(thiophen-2-ylmethyl)piperidin-4-yl)-4H-benzo[4,5]-
imidazo[1,2-b]pyrazole-8-carboxamide; 78)
3-(1-((1-ethylpiperidin-4-yl)methyl)-4-methylpiperidin-4-yl)-6-fluoro-4H--
benzo[4,5]imidazo[1, 2-b]pyrazole-8-carboxamide; 79)
6-fluoro-3-(4-methyl-1-((1-methylazetidin-3-yl)methyl)piperidin-4-yl)-4H--
benzo[4,5]imidazo[1, 2-b]pyrazole-8-carboxamide; 80)
ethyl2-((4-(8-carbamoyl-6-fluoro-4H-benzo[4,5]imidazo[1,2-b]pyrazol-3-yl)-
-4-methylpiperidin-1-yl)methyl)cyclopropanecarboxylate; 81)
3-(1-((2-(dimethylcarbamoyl)cyclopropyl)methyl)-4-methylpiperidin-4-yl)-6-
-fluoro-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide; 82)
6-fluoro-3-(1-isobutyl-4-methylpiperidin-4-yl)-4H-benzo[4,5]imidazo[1,2-b-
]pyrazole-8-carboxamide; 83)
6-fluoro-3-(4-methyl-1-((4-methylthiazol-5-yl)methyl)piperidin-4-yl)-4H-b-
enzo[4,5]imidazo[1, 2-b]pyrazole-8-carboxamide; 84)
6-fluoro-3-(4-methyl-1-((1-methyl-1H-imidazol-2-yl)methyl)piperidin-4-yl)-
-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide; 85)
3-(1-((1,2-dimethyl-1H-imidazol-5-yl)methyl)-4-methylpiperidin-4-yl)-6-fl-
uoro-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide 86)
3-(1'-ethyl-4-methyl-[1,4'-bipiperidin]-4-yl)-6-fluoro-4H-benzo[4,5]imida-
zo[1,2-b]pyrazole-8-carboxamide; 87)
6-fluoro-3-(4-methyl-1-((6-oxo-1,6-dihydropyridazin-3-yl)methyl)piperidin-
-4-yl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide; 88)
3-(1-(2-cyanoethyl)-4-methylpiperidin-4-yl)-6-fluoro-4H-benzo[4,5]imidazo-
[1,2-b]pyrazole-8-carboxamide; 89)
6-chloro-3-(1-ethyl-4-methylpiperidin-4-yl)-4H-benzo[4,5]imidazo[1,2-b]py-
razole-8-carboxamide; 90)
3-(1-ethyl-3-methylpyrrolidin-3-yl)-6-fluoro-4H-benzo[4,5]imidazo[1,2-b]p-
yrazole-8-carboxamide; 91)
3-(1,3-dimethylpyrrolidin-3-yl)-6-fluoro-4H-benzo[4,5]imidazo[1,2-b]pyraz-
ole-8-carboxamide; 92)
6-fluoro-3-(1-isopropyl-3-methylpyrrolidin-3-yl)-4H-benzo[4,5]imidazo[1,2-
-b]pyrazole-8-carboxamide; 93)
3-(1-(cyclopropylmethyl)-3-methylpyrrolidin-3-yl)-6-fluoro-4H-benzo[4,5]i-
midazo[1,2-b]pyrazole-8-carboxamide; 94)
6-fluoro-3-(3-methyl-1-(oxetan-3-yl)pyrrolidin-3-yl)-4H-benzo[4,5]imidazo-
[1,2-b]pyrazole-8-carboxamide; 95)
6-fluoro-3-(1-(2-fluoroethyl)-3-methylpyrrolidin-3-yl)-4H-benzo[4,5]imida-
zo[1,2-b]pyrazole-8-carboxamide; 96)
3-(1-((2,2-difluorocyclopropyl)methyl)-3-methylpyrrolidin-3-yl)-6-fluoro--
4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide; 97)
6-fluoro-3-(3-methyl-1-(2,2,2-trifluoroethyl)pyrrolidin-3-yl)-4H-benzo[4,-
5]imidazo[1,2-b]pyrazole-8-carboxamide; 98)
6-fluoro-3-(3-methyl-1-(2-(methylsulfonyl)ethyl)pyrrolidin-3-yl)-4H-benzo-
[4,5]imidazo[1,2-b]pyrazole-8-carboxamide; 99)
6-fluoro-3-(3-methyl-1-(3,3,3-trifluoropropyl)pyrrolidin-3-yl)-4H-benzo[4-
,5]imidazo[1,2-b]pyrazole-8-carboxamide; 100)
3-(1-((1-aminocyclopropyl)methyl)-3-methylpyrrolidin-3-yl)-6-fluoro-4H-be-
nzo[4,5]imidazo[1, 2-b]pyrazole-8-carboxamide; 101)
3-(1-((1-cyanocyclobutyl)methyl)-3-methylpyrrolidin-3-yl)-6-fluoro-4H-ben-
zo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide; 102)
3-(1-((1-cyanocyclopropyl)methyl)-3-methylpyrrolidin-3-yl)-6-fluoro-4H-be-
nzo[4,5]imidazo[1, 2-b]pyrazole-8-carboxamide; 103)
3-(1-(2-cyanoethyl)-3-methylpyrrolidin-3-yl)-6-fluoro-4H-benzo[4,5]imidaz-
o[1,2-b]pyrazole-8-carboxamide; 104)
3-(1-(cyclopropylmethyl)-3-methylazetidin-3-yl)-6-fluoro-4H-benzo[4,5]imi-
dazo[1,2-b]pyrazole-8-carboxamide; 105)
6-fluoro-3-(1-isopropyl-4-methylpiperidin-4-yl)-4H-benzo[4,5]imidazo[1,2--
b]pyrazole-8-carboxamide; 106)
6-fluoro-3-(4-methyl-1,1-dioxido-2H-thiopyran-4-yl)-4H-benzo[4,5]imidazo[-
1,2-b]pyrazole-8-carboxamide; 107)
3-(1,4-diethylpiperidin-4-yl)-6-fluoro-4H-benzo[4,5]imidazo[1,2-b]pyrazol-
e-8-carboxamide; 108)
3-(4-cyano-1-(cyclopropylmethyl)piperidin-4-yl)-6-fluoro-4H-benzo[4,5]imi-
dazo[1,2-b]pyrazole-8-carboxamide; 109)
3-(1-(cyclopropylmethyl)-4-(hydroxymethyl)piperidin-4-yl)-6-fluoro-4H-ben-
zo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide; 110) Methyl
4-(8-carbamoyl-6-fluoro-4H-benzo[4,5]imidazo[1,2-b]pyrazol-3-yl)-1-(cyclo-
propylmethyl)piperidine-4-carboxylate; 111)
3-(1-(cyclopropylmethyl)-4-methylpiperidin-4-yl)-6-fluoro-2-methyl-4H-ben-
zo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide; 112)
3-(1-ethyl-4-methylpiperidin-4-yl)-6-fluoro-2-methyl-4H-benzo[4,5]imidazo-
[1,2-b]pyrazole-8-carboxamide; 113)
6-fluoro-3-(1-isobutyl-4-methylpiperidin-4-yl)-2-methyl-4H-benzo[4,5]imid-
azo[1,2-b]pyrazole-8-carboxamide; 114)
6-fluoro-3-(1-isopropyl-4-methylpiperidin-4-yl)-2-methyl-4H-benzo[4,5]imi-
dazo[1,2-b]pyrazole-8-carboxamide; 115)
3-(1,4-dimethylpiperidin-4-yl)-6-fluoro-2-methyl-4H-benzo[4,5]imidazo[1,2-
-b]pyrazole-8-carboxamide; 116)
6-fluoro-3-(1-(2-hydroxy-2-methylpropyl)-4-methylpiperidin-4-yl)-2-methyl-
-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide; 117)
3-(1-ethyl-2,4-dimethylpiperidin-4-yl)-6-fluoro-2-methyl-4H-benzo[4,5]imi-
dazo[1,2-b]pyrazole-8-carboxamide; 118)
3-(1-ethyl-3-methylpyrrolidin-3-yl)-6-fluoro-2-methyl-4H-benzo[4,5]imidaz-
o[1,2-b]pyrazole-8-carboxamide; 119)
6-fluoro-3-(1-isopropyl-3-methylpyrrolidin-3-yl)-2-methyl-4H-benzo[4,5]im-
idazo[1,2-b]pyrazole-8-carboxamide; 120)
3-(1-(cyclopropylmethyl)-3-methylpyrrolidin-3-yl)-6-fluoro-2-methyl-4H-be-
nzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide; 121)
3-(1,3-dimethylazetidin-3-yl)-6-fluoro-2-methyl-4H-benzo[4,5]imidazo[1,2--
b]pyrazole-8-carboxamide; 122)
3-(1-ethyl-3-methylazetidin-3-yl)-6-fluoro-2-methyl-4H-benzo[4,5]imidazo[-
1,2-b]pyrazole-8-carboxamide; 123)
6-fluoro-3-(1-isopropyl-3-methylazetidin-3-yl)-2-methyl-4H-benzo[4,5]imid-
azo[1,2-b]pyrazole-8-carboxamide; 124)
3-(1-(cyclopropylmethyl)-3-methylazetidin-3-yl)-6-fluoro-2-methyl-4H-benz-
o[4,5]imidazo[1,2-b]pyrazole-8-carboxamide; 125)
6-fluoro-3-(1-(2-hydroxy-2-methylpropyl)-3-methylazetidin-3-yl)-2-methyl--
4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide; 126)
6-fluoro-3-(1-isopropyl-4-methylpiperidin-4-yl)-2-methoxy-4H-benzo[4,5]im-
idazo[1,2-b]pyrazole-8-carboxamide; 127)
2-(benzyloxy)-6-fluoro-3-(1-isopropyl-4-methylpiperidin-4-yl)-4H-benzo[4,-
5]imidazo[1,2-b]pyrazole-8-carboxamide; 128)
6-fluoro-2-(piperidin-4-yl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxa-
mide; and 129)
2-(1-ethylpiperidin-4-yl)-6-fluoro-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8--
carboxamide.
Definitions
C.sub.1-10 is selected from the group consisting of C.sub.1,
C.sub.2, C.sub.3, C.sub.4, C.sub.5, C.sub.6, C.sub.7, C.sub.8,
C.sub.9, and C.sub.10; C.sub.3-10 is selected from the group
consisting of C.sub.3, C.sub.4, C.sub.5, C.sub.6, C.sub.7, C.sub.8,
C.sub.9, and C.sub.10.
C.sub.1-10 alkyl, C.sub.1-10 heteroalkyl, C.sub.3-10
cyclohydrocarbyl, C.sub.3-10 heterocyclohydrocarbyl, C.sub.1-10
alkyl substituted by C.sub.3-10 cyclohydrocarbyl or C.sub.3-10
heterocyclohydrocarbyl, or C.sub.1-10 heteroalkyl substituted by
C.sub.3-10 cyclohydrocarbyl or C.sub.3-10 heterocyclohydrocarbyl
include, but are not limited to:
C.sub.1-10 alkyl, C.sub.1-10 alkylamino, N,N-di(C.sub.1-10 alkyl)
amino, C.sub.1-10 alkyloxyl, C.sub.1-10 alkylacyl, C.sub.1-10
alkyloxylcarbonyl, C.sub.1-10alkylsulfonyl, C.sub.1-10
alkylsulfinyl, C.sub.3-10 cycloalkyl, C.sub.3-10 cycloalkylamino,
C.sub.3-10 heterocycloalkylamino, C.sub.3-10 cycloalkyloxyl,
C.sub.3-10 cycloalkylacyl, C.sub.3-10 cycloalkyloxylcarbonyl,
C.sub.3-10 cycloalkylsulfonyl, and C.sub.3-10
cycloalkylsulfinyl;
methyl, ethyl, n-propyl, isopropyl,
--CH.sub.2C(CH.sub.3)(CH.sub.3)(OH), cyclopropyl, cyclobutyl,
propylmethylene, cycropropylacyl, benzyloxyl, trifluoromethyl,
aminomethyl, hydroxylmethyl, methyloxyl, formyl,
methyloxylcarbonyl, methylsulfonyl, methylsulfinyl, ethyloxyl,
acetyl, ethylsulfonyl, ethyloxylcarbonyl, dimethylamino,
diethylamino, dimethylaminocarbonyl, and diethylaminocarbonyl;
N(CH.sub.3).sub.2, NH(CH.sub.3), --CH.sub.2CF.sub.3,
--CH2CH.sub.2CF.sub.3, --CH.sub.2CH.sub.2F,
--CH.sub.2CH.sub.2S(.dbd.O).sub.2CH.sub.3,
--CH.sub.2CH.sub.2CN,
##STR00031##
--CH.sub.2CH(OH)(CH.sub.3).sub.2--CH.sub.2CH(F)(CH.sub.3).sub.2,
--CH.sub.2CH.sub.2F, --CH.sub.2CF.sub.3,
--CH.sub.2CH.sub.2CF.sub.3, --CH.sub.2CH.sub.2NH.sub.2,
--CH.sub.2CH.sub.2OH, --CH.sub.2CH.sub.2OCH.sub.3,
--CH.sub.2CH.sub.2CH.sub.2OCH.sub.3,
--CH.sub.2CH.sub.2N(CH.sub.3).sub.2, --S(.dbd.O).sub.2CH.sub.3,
--CH.sub.2CH.sub.2S(.dbd.O).sub.2CH.sub.3,
##STR00032## ##STR00033## ##STR00034## ##STR00035## ##STR00036##
##STR00037## ##STR00038## ##STR00039## ##STR00040##
##STR00041##
phenyl, thiazolyl, biphenyl, naphthyl, cyclopentyl, furyl,
3-pyrrolinyl, pyrrolidinyl, 1,3-oxolanyl, pyrazolyl, 2-pyrazolinyl,
pyrazolidinyl, imidazolyl, oxazolyl, thiazolyl, 1,2,3-oxadiazolyl,
1,2,3-triazolyl, 1,2,4-triazolyl, 1,3,4-thiadiazolyl, 4H-pyranyl,
pyridyl, piperidinyl, 1,4-dioxanyl, morpholinyl, pyridazinyl,
pyrimidinyl, pyrazinyl, piperazinyl, 1,3 5-trithianyl,
1,3,5-triazinyl, benzofuranyl, benzothienyl, indolyl,
benzimidazolyl, benzothiazolyl, purinyl, quinolinyl,
iso-quinolinyl, cinnolinyl, or quinoxalinyl;
The term "pharmaceutically acceptable" is employed herein to refer
to those compounds, materials, compositions, and/or dosage forms
which are, within the scope of sound medical judgment, suitable for
use in contact with the tissues of human beings and animals without
excessive toxicity, irritation, allergic response, or other
problems or complications, commensurate with a reasonable
benefit/risk ratio.
The term "pharmaceutically acceptable salt" is meant to include a
salt of a compound of the invention which is prepared by a
relatively nontoxic acid or base and the compound of the invention
having particular substituents. When the compound of the invention
contains a relatively acidic functional group, a base addition salt
can be obtained by contacting a neutral form of such compounds with
a sufficient amount of a desired base, either neat or in a suitable
inert solvent. Examples of the pharmaceutically acceptable base
addition salts include salts of sodium, potassium, calcium,
ammonium, organic amine, or magnesium, or similar salts. When the
compound of the invention contains a relatively basic functional
group, an acid addition salt can be obtained by contacting a
neutral form of such compounds with a sufficient amount of a
desired acid, either neat or in a suitable inert solvent. Examples
of the pharmaceutically acceptable acid addition salts include
salts of inorganic acids including hydrochloric, hydrobromic,
nitric, carbonic, hydrocarbonic, phosphoric, hydrophosphoric,
dihydrophosphoric, sulfuric, hydrosulfuric, hydriodic, or
phosphorous acids and the like; as well as salts of organic acids
including acetic, propionic, isobutyric, maleic, malonic, benzoic,
succinic, suberic, fumaric, lactic, mandelic, phthalic,
benzenesulfonic, p-tolylsulfonic, citric, tartaric, methanesulfonic
acid, or the like; and also salts of amino acids (such as arginate
and the like), and salts of organic acids like glucuronic acid and
the like (see, Berge et al., "Pharmaceutical Salts", Journal of
Pharmaceutical Science 66: 1-19 (1977)). Certain specific compounds
of the invention contain both basic and acidic functionalities that
allow the compounds to be converted into either base or acid
addition salts.
The neutral form of the compound is preferably regenerated by
contacting the salt with a base or acid and then isolating the
parent compound in the conventional manner. The parent form of the
compound differs from the various salt forms thereof in certain
physical properties, such as solubility in polar solvents.
As used herein, "pharmaceutically acceptable salts" refers to
derivatives of the compounds of the invention wherein the parent
compound is modified by making a salt with an acid or base.
Examples of pharmaceutically acceptable salts include, but are not
limited to, mineral or organic acid salts of basic groups such as
amines; alkali or organic salts of acidic groups such as carboxylic
acids; and the like. The pharmaceutically acceptable salts include
the conventional non-toxic salts or the quaternary ammonium salts
of the parent compound formed, for example, from non-toxic
inorganic or organic acids. Such conventional non-toxic salts
include, but are not limited to, those derived from inorganic and
organic acids selected from 2-acetoxybenzoic, 2-hydroxyethane
sulfonic, acetic, ascorbic, benzene sulfonic, benzoic, bicarbonic,
carbonic, citric, edetic, ethane disulfonic, ethane sulfonic,
fumaric, glucoheptonic, gluconic, glutamic, glycolic, hydrobromic,
hydrochloric, hydroiodide, hydroxyl acids, hydroxynaphthoic,
isethionic, lactic, lactobionic, lauryl sulfonic, maleic, malic,
mandelic, methane sulfonic, nitric, oxalic, pamoic, pantothenic,
phenylacetic, phosphoric, polygalacturonic, propionic, salicyclic,
stearic, subacetic, succinic, sulfamic, sulfanilic, sulfuric,
tannic, tartaric, and toluene sulfonic acid.
The pharmaceutically acceptable salts of the present invention can
be synthesized from the parent compound that contains a basic or
acidic moiety by conventional chemical methods.
Generally, such salts can be prepared by reacting the free acid or
base forms of these compounds with a stoichiometric amount of the
appropriate base or acid in water or in an organic solvent, or in a
mixture of the two; generally, non-aqueous media like ether, ethyl
acetate, ethanol, isopropanol, or acetonitrile or the like are
preferred.
In addition to salt forms, the present invention provides compounds
which are in a prodrug form. Prodrugs of the compounds described
herein readily undergo chemical changes under physiological
conditions to provide the compounds of the invention. Additionally,
prodrugs can be converted to the compounds of the invention by
chemical or biochemical methods in an in vivo environment.
Certain compounds of the invention can exist in unsolvated forms or
solvated forms, including hydrated forms. In general, the solvated
forms are equivalent to unsolvated forms and all are encompassed
within the scope of the present invention. Certain compounds of the
invention may exist in polycrystalline or amorphous forms.
Certain compounds of the invention may possess asymmetric carbon
atoms (optical centers) or double bonds; the racemates,
diastereomers, geometric isomers and individual isomers are all
encompassed within the scope of the present invention.
The graphic representations of racemic, ambiscalemic and scalemic
or enantiomerically pure compounds used herein are taken from
Maehr, J. Chem. Ed. 1985, 62: 114-120. Solid and broken wedges are
used to denote the absolute configuration of a stereocenter unless
otherwise noted. When the compounds described herein contain
olefinic double bonds or other centers of geometric asymmetry, and
unless specified otherwise, it is intended that the compounds
include both E and Z geometric isomers. Likewise, all tautomeric
forms are included within the scope of the invention.
Compounds of the invention can exist in particular geometric or
stereoisomeric forms. The invention contemplates all such
compounds, including cis- and trans-isomers, (-)- and
(+)-enantiomers, (R)- and (S)-enantiomers, diastereomers,
(D)-isomers, (L)-isomers, the racemic mixtures thereof, and other
mixtures thereof, such as enantiomerically or diastereomerically
enriched mixtures, and all these mixtures as falling within the
scope of the invention. Additional asymmetric carbon atoms can be
present in a substituent such as an alkyl group. All such isomers,
as well as mixtures thereof, are intended to be included in this
invention.
Optically active (R)- and (S)-isomers and D and L isomers can be
prepared by chiral synthons or chiral reagents, or other
conventional techniques. If a particular enantiomer of a compound
of the present invention is desired, it can be prepared by
asymmetric synthesis, or by derivatization with a chiral auxiliary,
where the resultant diastereomeric mixture is separated and the
auxiliary group is cleaved to provide the pure desired enantiomers.
Alternatively, where the molecule contains a basic functional group
(such as an amino group) or an acidic functional group (such as a
carboxyl group) diastereomeric salts can be formed with an
appropriate optically active acid or base, followed by resolution
of the diastereomers by fractional crystallization or
chromatographic means known in the art, and subsequent recovery of
the pure enantiomers. In addition, separation of enantiomers and
diastereomers is frequently accomplished by chromatography
employing chiral, stationary phases, optionally in combination with
chemical derivatization (e.g., formation of carbamates from
amines).
The compounds of the invention may also contain unnatural
proportions of atomic isotopes at one or more of the atoms that
constitute such compounds. For example, the compounds may be
radiolabeled with radioactive isotopes, such as for example tritium
(.sup.3H), iodine-125 (.sup.125I) or carbon-14 (.sup.14C). All
isotopic variations of the compounds of the invention, regardless
of radioactivity, are intended to be encompassed within the scope
of the present invention.
The term "pharmaceutically acceptable carrier or vehicle" refers to
any formulation or carrier medium that is capable of delivery of an
effective amount of an active agent of the invention without toxic
side effects on a host or patient. Representative carriers include
water, oils, both vegetable and mineral, cream bases, lotion bases,
ointment bases and the like. These bases include suspending agents,
thickeners, penetration enhancers, and the like. Their formulation
is well known to those in the art of cosmetics and topical
pharmaceuticals. Additional information concerning carriers can be
found in Remington: The Science and Practice of Pharmacy, 21st Ed.,
Lippincott, Williams & Wilkins (2005) which is incorporated
herein by reference.
The term "excipients" conventionally means carriers, diluents
and/or vehicles needed in formulating effective pharmaceutical
compositions.
The terms "effective amount" or "therapeutically effective amount"
for a drug or pharmacologically active agent refers to a nontoxic
but sufficient amount of the drug or agent to provide the desired
effect. In the oral dosage forms of the present disclosure, an
"effective amount" of an active agent of the composition refers to
the amount of the active agent required to provide the desired
effect when used in combination with the other active agent of the
composition. The amount that is "effective" will vary from subject
to subject, depending on the age and general condition of a
recipient, and also a particular active agent, and an appropriate
effective amount in an individual case may be determined by one of
ordinary skill in the art using routine experimentation.
The terms "active ingredient," "therapeutic agent," "active
substance," or "active agent" mean a chemical entity which can be
effective in treating a targeted disorder, disease or
condition.
The term "substituted" means that any one or more hydrogens on a
designated atom is replaced with a substituent including deuterium
and a variant of hydrogen, provided that the designated atom's
valency is normal, and that the substituted compound is stable.
When a substituent is keto (i.e., .dbd.O), it means that 2 hydrogen
atoms are replaced. Keto substituents are not present on aromatic
moieties. The term "optionally substituted" means that the
designated atom can be substituted or unsubstituted, and unless
otherwise stated, the species and number of the substituents may be
arbitrary provided that they can be achieved in Chemistry.
When any variable (e.g., R) occurs more than once in the
constituent or structure of a compound, its definition at each
occurrence is independent. Thus, for example, if a group is
substituted with 0-2 Rs, then said group may optionally be
substituted with up to two R groups and R at each occurrence has
independent options. Also, combinations of substituents and/or
variables are permissible only if such combinations result in
stable compounds.
When a bond to a substituent is shown to cross a bond connecting
two atoms in a ring, then such substituent may be bonded to any
atom on the ring. When a substituent is listed without indicating
via which atom such substituent is bonded to the compound of a
general formula including unspecified ones, then such substituent
may be bonded via any atom therein. Combinations of substituents
and/or variables are permissible only if such combinations result
in stable compounds.
Substituents of the alkyl and heteroalkyl radicals (including those
groups often referred to as alkylene, alkenyl, heteroalkylene,
heteroalkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl,
and heterocycloalkenyl) are generically referred to as "alkyl group
substituents," and they can be one or more selected from, but not
limited to the following groups: --R', --OR', .dbd.O, .dbd.NR',
.dbd.N--OR', --NR'R'', --SR', -halogen, --SiR'R''R''', OC(O)R',
--C(O)R', --CO.sub.2R', --CONR'R'', --OC(O)NR'R'', --NR''C(O)R',
NR'C(O)NR''R''', --NR''C(O).sub.2R',
--NR'''''-C(NR'R''R''').dbd.NR'''', NR'''' C(NR'R'').dbd.NR''',
--S(O)R', --S(O).sub.2R', --S(O).sub.2NR'R'', NR''SO.sub.2R', --CN,
--NO.sub.2, --N.sub.3, --CH(Ph).sub.2, and
fluoro(C.sub.1-C.sub.4)alkyl, with a number of substitutents
ranging from zero to (2m'+1), where m' is the total number of
carbon atoms in such radical. R', R'', R''', R'''' and R''''' are
each preferably independently hydrogen, substituted or
unsubstituted heteroalkyl, substituted or unsubstituted aryl (e.g.,
aryl substituted with 1-3 halogens), substituted or unsubstituted
alkyl, alkoxy or thioalkoxy groups, or arylalkyl groups. When a
compound of the invention includes more than one R group, for
example, each of the R groups is independently selected as are each
R', R'', R''', R'''' and R''''' groups when more than one of these
groups is present. When R' and R'' are attached to the same
nitrogen atom, they can be combined with the nitrogen atom to form
a 5-, 6-, or 7-membered ring. For example, --NR'R'' is meant to
include, but not be limited to, 1-pyrrolidinyl and 4-morpholinyl.
From the above discussion on substituents, one of skill in the art
will understand that the term "alkyl" is meant to include groups
constituted by carbon atoms bonding to groups other than hydrogen
groups, such as haloalkyl (e.g., --CF.sub.3 and --CH.sub.2CF.sub.3)
and acyl (e.g., --C(O)CH.sub.3, --C(O)CF.sub.3,
--C(O)CH.sub.2OCH.sub.3, and the like).
Similar to the substituents described for the alkyl radical,
substituents of the aryl and heteroaryl groups are generically
referred to as "aryl group substituents." The substituents are
selected from, for example: --R', --OR', --NR'R'', --SR', -halogen,
--SiR'R''R''', OC(O)R', --C(O)R', --CO2R', --CONR'R'',
--OC(O)NR'R'', --NR''C(O)R', NR'C(O)NR''R''', --NR''C(O).sub.2R',
--NR'''''--C(NR'R''R''').dbd.NR'''', NR'''' C(NR'R'').dbd.NR''',
--S(O)R', --S(O).sub.2R', --S(O).sub.2NR'R'', NR''SO.sub.2R', --CN,
--NO.sub.2, --N.sub.3, --CH(Ph).sub.2,
fluoro(C.sub.1-C.sub.4)alkoxy, and fluoro(C.sub.1-C.sub.4)alkyl,
etc., with a number of substitutents ranging from zero to the total
number of open valences on the aromatic ring; where R', R'', R''',
R'''' and R''''' are preferably independently selected from
hydrogen, substituted or unsubstituted alkyl, substituted or
unsubstituted heteroalkyl, substituted or unsubstituted aryl and
substituted or unsubstituted heteroaryl. When a compound of the
invention includes more than one R group, for example, each of the
R groups is independently selected as are each R', R'', R''', R''''
and R''''' groups when more than one of these groups is
present.
Two of the substituents on adjacent atoms of the aryl or heteroaryl
ring may optionally be replaced with a substituent of the formula
-T-C(O)--(CRR')q-U--, wherein T and U are independently selected
from --NR--, --O--, --CRR'-- or a single bond, and q is an integer
from 0 to 3.
Alternatively, two of the substituents on adjacent atoms of the
aryl or heteroaryl ring may optionally be replaced with a
substituent of the formula -A(CH.sub.2)rB--, wherein A and B are
independently selected from --CRR'--, --O--, --NR--, --S--,
--S(O)--, --S(O).sub.2--, --S(O).sub.2NR'-- or a single bond, and r
is an integer from 1 to 4. One of the single bonds of the thus
formed new ring may optionally be replaced with a double bond.
Alternatively, two of the substituents on adjacent atoms of the
aryl or heteroaryl ring may optionally be replaced with a
substituent of the formula -A(CH.sub.2)rB--, where s and d are
separately and independently selected from integers from 0 to 3,
and X is --O--, --NR'--, --S--, --S(O)--, --S(O).sub.2--, or
--S(O).sub.2NR'--. The substituents R, R', R'' and R''' are
separately, preferably and independently selected from hydrogen and
substituted or unsubstituted (C.sub.1-C.sub.6)alkyl.
The term "hydrocarbyl" or its hyponyms (such as alkyl, alkenyl,
alkynyl and phenyl etc.) by itself or as part of another
substituent, means, unless otherwise stated, a straight or branched
chain, or cyclic hydrocarbon radical, or combination thereof, which
may be fully saturated, mono- or polyunsaturated, and may be mono-,
di-, or multi-substituted, and can include di- or multi-valent
radicals, having the designated number of carbon atoms (e.g.,
C.sub.1-C.sub.10 meaning one to ten carbons). "Hydrocarbyl"
include, but are not limited to, aliphatic hydrocarbyl and aromatic
hydrocarbyl, and the aliphatic hydrocarbyl include linear and
cyclic ones, specifically including but not limited to, alkyl,
alkenyl, and alkynyl, and the aromatic hydrocarbyl include, but are
not limited to, 6-12 membered aromatic hydrocarbyl, for example,
benzene, and naphthalene, etc. In some embodiments, the term
"alkyl" means a straight or branched chain radical, or combinations
thereof, which may be fully saturated, mono- or polyunsaturated and
can include di- and multivalent radicals. Examples of saturated
hydrocarbon radicals include, but are not limited to, methyl,
ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl,
isobutyl, cyclohexyl, (cyclohexyl)methyl, cyclopropylmethyl,
homologs and isomers of radicals such as n-pentyl, n-hexyl,
n-heptyl, n-octyl, and the like. An unsaturated alkyl group is one
having one or more double bonds or triple bonds. Examples of
unsaturated alkyl groups include, but are not limited to, vinyl,
2-propenyl, butenyl, crotyl, 2-isopentenyl, 2-(butadienyl),
2,4-pentadienyl, 3-(1,4-pentadienyl), ethynyl, 1- and 3-propynyl,
3-butynyl, and the higher homologs and isomers.
The term "heterohydrocarbyl" or its hyponymshyponyms (such as
heteroalkyl, heteroalkenyl, heteroalkynyl and heteroaryl etc.) by
itself or in combination with another term, means, unless otherwise
stated, a stable straight or branched chain, or cyclic hydrocarbon
radical, or combinations thereof, consisting of the stated number
of carbon atoms and at least one heteroatom. In some embodiments,
the term "heteroalkyl," by itself or in combination with another
term, means a stable straight or branched chain hydrocarbyl
radical, or combinations thereof, consisting of the stated number
of carbon atoms and at least one heteroatom. In a typical
embodiment, the heteroatoms are selected from the group consisting
of B, O, N and S, wherein the nitrogen and sulfur atoms may
optionally be oxidized and the nitrogen heteroatom may optionally
be quaternized. The heteroatom(s) B, O, N and S may be placed at
any internal position of the heterohydrocarbyl group (except the
position at which the hydrocarbyl group is attached to the
remainder of the molecule). Examples include, but are not limited
to, --CH.sub.2--CH.sub.2--O--CH.sub.3,
--CH.sub.2--CH.sub.2--NH--CH.sub.3,
--CH.sub.2--CH.sub.2--N(CH.sub.3)--CH.sub.3,
--CH.sub.2--S--CH.sub.2--CH.sub.3, --CH.sub.2--CH.sub.2,
--S(O)--CH.sub.3, --CH.sub.2--CH.sub.2--S(O).sub.2--CH.sub.3,
--CH.dbd.CH--O--CH.sub.3, --CH.sub.2--CH.dbd.N--OCH.sub.3, and
--CH.dbd.CH--N(CH.sub.3)--CH.sub.3. Up to two heteroatoms may be
consecutive, such as, for example, --CH.sub.2--NH--OCH.sub.3.
The terms "alkoxy," "alkylamino" and "alkylthio" (or thioalkoxy)
are used in their conventional sense, and refer to those alkyl
groups attached to the remainder of the molecule via an oxygen
atom, an amino group, or a sulfur atom, respectively.
The terms "cyclohydrocarbyl," "heterocyclohydrocarbyl" or
"cyclohydrocarbylheteroyl" or its hyponyms (such as aryl,
heteroaryl, arylheteroyl, cycloalkyl, heterocycloalkyl,
cycloalkylheteroyl, cycloalkenyl, heterocycloalkenyl,
cycloalkenylheteroyl, cycloalkynyl, heterocycloalkynyl and
cycloalkynylheteroyl, etc.) by themselves or in combination with
other terms, represent, unless otherwise stated, cyclic versions of
"hydrocarbyl," "heterohydrocarbyl" or "hydrocarbylheteroyl,"
respectively. Additionally, for heterohydrocarbyl or
heterocyclohydrocarbyl (such as heteroalkyl and heterocycloalkyl),
a heteroatom can occupy the position at which the heterocycle is
attached to the remainder of the molecule. Examples of cycloalkyl
include, but are not limited to, cyclopentyl, cyclohexyl,
1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl, and the like.
Non-limiting examples of heterocycle moieties include
1-(1,2,5,6-tetrahydropyridyl), 1-piperidinyl, 2-piperidinyl,
3-piperidinyl, 4-morpholinyl, 3-morpholinyl, tetrahydrofuran-2-yl,
tetrahydrofuranindol-3-yl, tetrahydrothien-2-yl,
tetrahydrothien-3-yl, 1-piperazinyl, and 2-piperazinyl.
The term "halo" or "halogen," by themselves or as part of another
substituent, means, unless otherwise stated, a fluorine, chlorine,
bromine, or iodine atom. Additionally, the term "haloalkyl," are
meant to include monohaloalkyl and polyhaloalkyl. For example, the
term "halo(C.sub.1-C.sub.4)alkyl" is mean to include, but not be
limited to, trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl,
3-bromopropyl, and the like.
The term "aryl" means, unless otherwise stated, a polyunsaturated,
aromatic substituent that may be mono-, di- or poly-substituted,
and can be a single ring or multiple rings (preferably from 1 to 3
rings), which are fused together or linked covalently. The term
"heteroaryl" refers to aryl groups (or rings) that contain from one
to four heteroatoms. In an exemplary embodiment, the heteroatom is
selected from B, N, O, and S, wherein the nitrogen and sulfur atoms
are optionally oxidized, and the nitrogen atom(s) are optionally
quaternized. A heteroaryl group can be attached to the remainder of
the molecule through a heteroatom. Non-limiting examples of aryl
and heteroaryl groups include phenyl, 1-naphthyl, 2-naphthyl,
4-biphenyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 3-pyrazolyl,
2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl,
2-phenyl-4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl,
5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furyl,
3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl,
2-pyrimidyl, 4-pyrimidyl, 5-benzothiazolyl, purinyl,
2-benzimidazolyl, 5-indolyl, 1-isoquinolyl, 5-isoquinolyl,
2-quinoxalinyl, 5-quinoxalinyl, 3-quinolyl, and 6-quinolyl.
Substituents of any of the above-described aryl and heteroaryl ring
systems are selected from the acceptable substituents described
below.
For brevity, the term "aryl" when used in combination with other
terms (e.g., aryloxy, arylthio, arylalkyl) includes both aryl and
heteroaryl rings as defined above. Thus, the term "arylalkyl" is
meant to include those radicals in which an aryl group is attached
to an alkyl group (e.g., benzyl, phenethyl, pyridylmethyl and the
like) including those alkyl groups in which a carbon atom (e.g., a
methylene group) has been replaced by, for example, an oxygen atom,
e.g., phenoxymethyl, 2-pyridyloxymethyl, 3-(1-naphthyloxy)propyl,
and the like.
"Ring or cyclo" means a substituted or unsubstituted cycloalkyl,
substituted or unsubstituted heterocycloalkyl, substituted or
unsubstituted aryl, or substituted or unsubstituted heteroaryl. The
so-called ring includes fused ring moieties. The number of atoms in
a ring is typically defined as the number of members of the ring.
For example, a "5- to 7-membered ring" means there are 5 to 7 atoms
in the encircling arrangement. Unless otherwise specified, the ring
optionally includes one to three heteroatoms. Thus, the term "5- to
7-membered ring" includes, for example phenyl, pyridinyl and
piperidinyl. The term "5- to 7-membered heterocycloalkyl ring," on
the other hand, include pyridinyl and piperidinyl, but not phenyl.
The term "ring" further includes a ring system comprising at least
one ring, wherein each "ring" is independently defined as
above.
As used herein, the term "heteroatom" includes atoms other than
carbon (C) and hydrogen (H), including e.g., oxygen (O), nitrogen
(N) sulfur (S), silicon (Si), germanium (Ge), aluminum (Al) and
boron (B), etc.
The term "leaving group" means a functional group or atom which can
be displaced by another functional group or atom in a substitution
reaction (such as a nucleophilic substitution reaction). For
example, representative leaving groups include triflate, chloro,
bromo and iodo groups; sulfonic ester groups, such as mesylate,
tosylate, brosylate, nosylate and the like; and acyloxy groups,
such as acetoxy, trifluoroacetoxy and the like.
The term "protecting group" includes but is not limited to
"amino-protecting group," "hydroxy-protecting group" or
"thiol-protecting group." The term "amino-protecting group" means a
protecting group suitable for preventing side reactions at an amino
nitrogen. Representative amino-protecting groups include, but are
not limited to, formyl; acyl groups, for example alkanoyl groups,
such as acetyl, trichloroacetyl or trifluoroacetyl; alkoxycarbonyl
groups, such as tert-butoxycarbonyl (Boc); arylmethoxycarbonyl
groups, such as benzyloxycarbonyl (Cbz) and
9-fluorenylmethoxycarbonyl (Fmoc); arylmethyl groups, such as
benzyl (Bn), trityl (Tr), and 1,1-di-(4'-methoxyphenyl)methyl;
silyl groups, such as trimethylsilyl (TMS) and
tert-butyldimethylsilyl (TBS); and the like. The term
"hydroxy-protecting group" means a protecting group suitable for
preventing side reactions at a hydroxy group. Representative
hydroxy-protecting groups include, but are not limited to, alkyl
groups, such as methyl, ethyl, and tert-butyl; acyl groups, for
example alkanoyl groups, such as acetyl; arylmethyl groups, such as
benzyl (Bn), p-methoxybenzyl (PMB), 9-fluorenylmethyl (Fm), and
diphenylmethyl (benzhydryl, DPM); silyl groups, such as
trimethylsilyl (TMS) and tert-butyldimethylsilyl (TBS); and the
like.
Examples of haloalkyl include, but are not limited to,
trifluoromethyl, trichloromethyl, pentafluoroethyl, and
pentachloroethyl. "Alkoxy" represents an alkyl group as defined
above with the indicated number of carbon atoms attached through an
oxygen bridge. C.sub.1-6 alkoxy is intended to include C.sub.1,
C.sub.2, C.sub.3, C.sub.4, C.sub.5, and C.sub.6 alkoxy groups.
Examples of alkoxy include, but are not limited to, methoxy,
ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy, t-butoxy,
n-pentoxy, and s-pentoxy. "Cycloalkyl" is intended to include
saturated ring groups, such as cyclopropyl, cyclobutyl, or
cyclopentyl. 3-7 cycloalkyl is intended to include C.sub.3,
C.sub.4, C.sub.5, C.sub.6, and C.sub.7 cycloalkyl groups. "Alkenyl"
is intended to include hydrocarbon chains of either straight or
branched configuration and one or more unsaturated carbon-carbon
bonds that may occur in any stable point along the chain, such as
ethenyl and propenyl. The term "Halo" or "halogen" refers to
fluoro, chloro, bromo, and iodo.
The term "heterocycle" or "heterocyclo" is intended to mean a
stable monocyclic or bicyclic or bicyclic heterocyclic ring which
may be saturated, partially unsaturated or unsaturated (aromatic),
and include carbon atoms and 1, 2, 3, or 4 ring heteroatoms
independently selected from the group consisting of N, O and S in
which any of the above-defined heterocyclic rings may be fused to a
benzene ring to form a bicyclic group. The nitrogen and sulfur
heteroatoms may optionally be oxidized (i. e., NO and S(O) p). The
nitrogen atom may be substituted or unsubstituted (i.e., N or NR
wherein R is H or other substituents already defined herein). The
heterocyclic ring may be attached to its pendant group at any
heteroatom or carbon atom that results in a stable structure. The
heterocyclic rings described herein may be substituted on a carbon
or on a nitrogen atom if the resultant compound is stable. A
nitrogen atom in the heterocycle may optionally be quaternized. In
a preferred embodiment, when the total number of S and O atoms in
the heterocycle exceeds 1, then these heteroatoms are not adjacent
to one another. In another preferred embodiment, the total number
of S and O atoms in the heterocycle is not more than 1. As used
herein, the term "aromatic heterocyclic group" or "heteroaryl" is
intended to mean a stable 5-, 6-, or 7-membered monocyclic or
bicyclic or 7-, 8-, 9-, or 10-membered bicyclic heterocyclic
aromatic ring which includes carbon atoms and 1, 2, 3, or 4
heteroatoms independently selected from the group consisting of N,
O and S. The nitrogen atom may be substituted or unsubstituted
(i.e., N or NR wherein R is H or other substituents already defined
herein). The nitrogen and sulfur heteroatoms may optionally be
oxidized (i.e., NO and S(O) p). It is to be noted that total number
of S and O atoms in the aromatic heterocycle is not more than 1.
Bridged rings are also included in the definition of heterocycle. A
bridged ring occurs when one or more atoms (i.e., C, O, N, or S)
link two non-adjacent carbon or nitrogen atoms. Preferred bridged
rings include, but are not limited to, one carbon atom, two carbon
atoms, one nitrogen atom, two nitrogen atoms, and a carbon-nitrogen
group. It is to be noted that a bridge always converts a monocyclic
ring into a tricyclic ring. In a bridged ring, the substituents on
the ring may also be present on the bridge.
Examples of heterocycles include, but are not limited to,
acridinyl, azocinyl, benzimidazolyl, benzofuranyl,
benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzoxazolinyl,
benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl,
benzisothiazolyl, benzimidazolinyl, carbazolyl, 4aH-carbazolyl,
carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl,
2H,6H-1, 5,2-dithiazinyl, dihydrofuro [2, 3-b]tetrahydrofuran,
furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl,
1H-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl,
3H-indolyl, isatinoyl, isobenzofuranyl, isochromanyl, isoindazolyl,
isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl,
methylenedioxyphenyl, morpholinyl, naphthyridinyl,
octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl,
1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl,
oxazolidinyl, oxazolyl, oxindolyl, pyrimidinyl, phenanthridinyl,
phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathinyl,
phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, piperidonyl,
4-piperidonyl, piperonyl, pteridinyl, purinyl, pyranyl, pyrazinyl,
pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole,
pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl,
pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl,
quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl,
tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl,
tetrazolyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,
4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl,
thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl,
thienoimidazolyl, thiophenyl, triazinyl, 1,2, 3-triazolyl,
1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, and xanthenyl.
Also included are fused ring and spiro compounds.
The compounds of the present invention can be prepared in a number
of synthetic methods known to one skilled in the art, including the
specific embodiments described below, the embodiments formed by
combining them with other chemical synthetic methods known in the
art, and equivalents well known to those skilled in the art.
Preferred embodiments include, but are not limited to, examples of
the invention.
All solvents used herein are commercially available and are used
without further purification. Reactions are typically run in
anhydrous solvents under an inert atmosphere of nitrogen. Proton
NMR data are recorded on Bruker Avance III 400 (400 MHz)
spectrometer and chemical shifts are reported as .delta. (ppm) down
field from tetramethylsilane. Mass spectra are determined on
Agilent 1200 series plus 6110 (& 1956A). LC/MS, or Shimadzu MS
includes a DAD:SPD-M20A (LC) and Shimadzu Micromass 2020 detector.
The mass spectrometer is equipped with an electrospray ion source
(ESI) operated in a positive or negative mode.
The following abbreviations are used herein: aq represents aqueous;
HATU represents
O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium
hexafluorophosphate; EDC represents
N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride,
m-CPBA represents 3-chloroperoxybenzoic acid; eq. represents
equivalent; CDI represents carbonyl diimidaole; DCM represents
dichloromethane; PE represents petroleum ether; DIAD represents
diisopropyl azodicarboxylate; DMF represents N,N-dimethylformamide;
DMSO represents dimethylsulfoxide; EtOAc represents ethyl acetate;
EtOH represents ethanol; MeOH represents methanol; CBz represents
benzyloxycarbonyl, a amine protecting group; BOC represents
tert-butylcarbonyl, an amine protecting group; HOAc represents
acetic acid; NaCNBH.sub.3 represents sodium cyanoborohydride; r.t.
represents room temperature; O/N represents overnight; THF
represents tetrahydrofuran; Boc.sub.2O represents di-tert-butyl
dicarbonate; TFA represents trifluoroacetic acid; DIPEA represents
diisopropylethylamine; SOCl.sub.2 represents sulfurous dichloride;
CS.sub.2 represents carbon disulfide; TsOH represents
4-methylbenzenesulfonic acid; NFSI represents
N-fluoro-N-(phenylsulfonyl)benzenesulfonamide; NCS represents
N-chlorosuccinimide; n-Bu.sub.4NF represents tetrabutylammonium
fluoride; i-PrOH represents 2-propanol and mp represents melting
point.
Compounds were named either manually or by using ChemDraw.RTM., or
using vendors catalogue name if commercially available.
HPLC analyses were performed on a Shimadzu LC20AB system with a
Shimadzu SIL-20A Autosampler and a Shimadzu DAD:SPD-M20A Detector.
The column used was a Xtimate C18, 3 .mu.m, 2.1.times.300 mm.
Method 0-60AB_6 min included: applying a linear gradient, starting
elution at 100% A (A: 0.0675% TFA in water) and ending elution at
60% B (B: 0.0625% TFA in MeCN) overall for 4.2 min and then eluting
at 60% B for 1.0 min. The column was then re-equilibrated over 0.8
min to 100:0 with a total run time of 6 min. Method 10-80AB_6 min
included: applying a linear gradient, starting elution at 90% A (A:
0.0675% TFA in water) and ending elution at 80% B (B: 0.0625% TFA
in MeCN) overall for 4.2 min and then eluting at 80% B for 1.0 min.
The column was then re-equilibrated over 0.8 min to 90:10 with a
total run time of 6 min. The column temperature was at 50.degree.
C. with a flow rate of 0.8 mL/min. The Diode Array Detector scanned
from 200-400 nm.
Thin layer chromatography (TLC) was performed on Silica gel GF254
from Sanpont-group and UV was typically used to visualize the
spots. Additional visualization methods were also employed in some
cases. In these cases the TLC plate was developed with iodine
(prepared by adding approximately 1 g of I.sub.2 to 10 g silica gel
and thoroughly mixing), vanillin (prepared by dissolving about 1 g
vanillin in 100 mL 10% H.sub.2SO.sub.4), ninhydrin (available
commercially from Aldrich), or Magic Stain (prepared by thoroughly
mixing (NH.sub.4).sub.6Mo.sub.7O.sub.24.4H.sub.2O, 5 g
(NH.sub.4).sub.2Ce(IV)(NO.sub.3).sub.6, 450 mL H.sub.2O and 50 mL
concentrated H.sub.2SO.sub.4) to visualize the compound. Flash
chromatography was performed using 40-63 .mu.m (230-400 mesh)
silica gel from Silicycle following analogous techniques to those
disclosed in Still, W. C.; Kahn, M.; and Mitra, M. Journal of
Organic Chemistry, 1978, 43, 2923-2925. Typical solvents used for
flash chromatography or thin layer chromatography were mixtures
such as dichloromethane/methanol, ethyl acetate/methanol and
hexanes/ethyl acetate.
Preparative chromatography was performed on a Gilson-281 Prep LC
322 System using a Gilson UV/VIS-156 Detector. The column used was
a Agella Venusil ASB Prep C18, 5 .mu.m, 150.times.21.2 mm or
Phenomenex Gemini C18, 5 .mu.m, 150.times.30 mm or Boston Symmetrix
C18, 5 .mu.m, 150.times.30 mm or Phenomenex Synergi C18, 4 .mu.m,
150.times.30 mm. Narrow gradients with acetonitrile/water, with the
water containing 0.05% HCl or 0.25% HCOOH or 0.5%
NH.sub.3.H.sub.2O, were used to elute the compounds at a flow rate
of approximately 25 mL/min and a total run time of 8-15 min.
SFC analyses were performed on an Agilent 1260 Infinity SFC system
with an Agilent 1260 Autosampler and an Agilent DAD:1260 Detector.
The column used was Chiralcel OD-H 250.times.4.6 mm I.D., 5 um or
Chiralpak AS-H 250.times.4.6 mm I.D., 5 .mu.m or Chiralpak AD-H
250.times.4.6 mm I.D., 5 um. Method OD-H_5_40_2.35 ML Column
included: Chiralcel OD-H 250.times.4.6 mm I.D., 5 .mu.m Mobile
phase: 40% ethanol (0.05% DEA) in CO.sub.2 Flow rate: 2.35 mL/min
Wavelength: 220 nm. Method AS-H_3_40_2.35 ML Column included:
Chiralpak AS-H 250.times.4.6 mm I.D., 5 .mu.m Mobile phase: 40%
methanol (0.05% DEA) in CO.sub.2 Flow rate: 2.35 mL/min Wavelength:
220 nm. Method OD-H_3_40_2.35M Column included: Chiralcel OD-H
250.times.4.6 mm I.D., 5 .mu.m Mobile phase: 40% methanol (0.05%
DEA) in CO.sub.2 Flow rate: 2.35 mL/min Wavelength: 220 nm. Method
AD-H_2_50_2.35 ML Column included: Chiralpak AD-H 250.times.4.6 mm
I.D., 5 mm Mobile phase: 50% methanol (0.1% MEA) in CO.sub.2 Flow
rate: 2.35 mL/min Wavelength: 220 nm.
Preparative SFC analysis was performed on a Waters Thar 80 Pre-SFC
System using a Gilson UV Detector. The column used was Chiralcel
OD-H 250.times.4.6 mm I.D., 5 m or Chiralpak AD-H 250.times.4.6 mm
I.D., 5 m. Narrow gradients with ethanol or methanol in CO.sub.2,
with the ethanol or methanol containing 0.05% NH.sub.3.H.sub.2O or
0.05% DEA or 0.1% MEA, were used to elute the compound at a flow
rate between 40-80 mL/min and a total run time between 20-30
min.
The PARP-1 inhibitors provided herein can be used for the treatment
of wide rages of diseases comprising cancer, stroke, cardiac
ischemia, inflammation, and diabetes. The PARP-1 inhibitors can be
used as a standalone agent or in combination with other
chemotherapeutical agents to enhance the effect of these standard
chemotherapeutical agents.
Cancers that can be treated by the PARP-1 inhibitors include, but
are not limited to breast cancer, ovarian cancer, pancreatic
cancer, prostate cancer, clone cancer, and leukemia, etc.
DETAILED DESCRIPTION OF THE INVENTION
To describe the present invention in more detail, the following
examples are provided. However, the scope of the present invention
is not limited to these.
##STR00042##
Example 1
6-fluoro-3-(piperidin-4-yl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxam-
ide
##STR00043##
Example 1A
tert-butyl 4-((tosyloxy)methyl)piperidine-1-carboxylate
##STR00044##
To a solution of tert-butyl
4-(hydroxymethyl)piperidine-1-carboxylate (10 g, 46.5 mmol),
Et.sub.3N (5.64 g, 55.8 mmol) and DMAP (1.13 g, 9.3 mmol) in DCM
(100 mL) was added in protions TosCl (9.73 g, 51.2 mmol) at
0.degree. C. under N.sub.2 atmosphere. After stirring at 17.degree.
C. for 2 h, water (100 mL) was added to quench. The aqueous layer
was extracted with DCM (100 mL.times.2). The combined organic
layers were dried over Na.sub.2SO.sub.4, filtered and evaporated to
give the residue which was purified by column chromatography to
give the title compound (17 g, 99% yield) as a white solid. LCMS
(ESI) m/z: 370 (M+1).
Example 1B
tert-butyl 4-(cyanomethyl)piperidine-1-carboxylate
##STR00045##
A mixture of EXAMPLE 1A (19 g, 55.7 mmol), sodium cyanide (8.19 g,
167 mmol) in dimethylsulfoxide (100 mL) was reacted at 100.degree.
C. for 16 h. After being cooled to room temperature, the mixture
was diluted with water (200 ml). The aqueous layer was extracted
with EtOAc (100 mL.times.3). The combined organic layers were
washed with water (50 mL), and brine (50 mL), then dried over
Na.sub.2SO.sub.4, filtered and evaporated to provide the title
compound (11 g) which could be used directly in the next step
without further purification. LCMS (ESI) m/z: 225 (M+1)
Example 1C
tert-butyl 4-(1-cyano-2-oxoethyl)piperidine-1-carboxylate
##STR00046##
To a mixture of EXAMPLE 1B (11 g, 49 mmol), t-BuOK (32.9 g, 294
mmol) in DMF (80 mL) was added dropwise a solution of ethyl formate
(21.7 g, 294 mmol) in DMF (50 mL) at -10.degree. C. under N.sub.2
atmosphere. After the dropwise addition completed, the mixture was
stirred at 17.degree. C. for 16 h, and then neutralized with 1N
HCl. The aqueous layer was extracted with EtOAc (100 mL.times.4).
The combined organic layers were dried over Na.sub.2SO.sub.4,
filtered and evaporated to provide the title compound (11 g, 89%)
which could be used directly in the next step without further
purification. LCMS (ESI) m/z: 253 (M+1)
Example 1D
(2,6-dibromo-4-fluorophenyl)hydrazine
##STR00047##
To a solution of 2,6-dibromo-4-fluoroaniline (5 g, 18.6 mmol) in 35
ml 20% aq HCl (35 mL) was added dropwise a solution of NaNO.sub.2
(1.41 g, 20.45 mmol) in water (40 mL) at -5.degree. C. with a rate
of the dropwise addition to keep the internal temperature below
5.degree. C. After 0.5 h, the above-mentioned solution was added
dropwise into a solution of SnCl.sub.2 (10.49 g, 46 mmol) in
concentrate HCl solution (40 mL) at -15.degree. C. After the
dropwise addition completed, the mixture was allowed to warm to
35.degree. C. and stirred for 12 h. The mixture was cooled to
0.degree. C. and adjusted to pH=9 with concentrate ammonia aqueous
solution. The aqueous layer was extracted with EtOAc (150
mL.times.3). The organic layers were washed with water (100 mL),
dried over Na.sub.2SO.sub.4, filtered and evaporated to give the
residue which was purified by column chromatography to provide the
title compound (4 g, yield: 76%). .sup.1H NMR (400 MHz, CDCl3-d):
.delta. ppm 3.91 (br. s., 1H), 5.37 (br. s., 1H), 7.31 (d, J=7.37
Hz, 2H).
Example 1E
tert-butyl
4-(1-cyano-2-(2-(2,6-dibromo-4-fluorophenyl)hydrazono)ethyl)pip-
eridine-1-carboxylate
##STR00048##
A mixture of EXAMPLE 1C (3.5 g, 13.87 mmol) and EXAMPLE 1D (3.94 g,
13.87 mmol) in EtOH (30 mL) was stirred at 80.degree. C. for 0.5 h.
After removal of solution in vacuum, the residue was purified by
column chromatography to provide the title compound as a white
solid (3.8 g, 53%). LCMS (ESI) m/z: 519 (M+1).
Example 1F
tert-butyl
4-(5-amino-1-(2,6-dibromo-4-fluorophenyl)-1H-pyrazol-4-yl)piper-
idine-1-carboxylate
##STR00049##
A mixture of EXAMPLE 1E (3.8 g, 7.33 mmol) and Et.sub.3N (1.48 g,
14.67 mmol) in EtOH (30 mL) was stirred at 80.degree. C. for 16 h.
The mixture was evaporated under vacuum to provide the title
compound which could be used directly in the next step without
further purification. (3.8 g, 100%).
Example 1G
tert-butyl
4-(8-bromo-6-fluoro-4H-benzo[4,5]imidazo[1,2-b]pyrazol-3-yl)pip-
eridine-1-carboxylate
##STR00050##
A mixture of EXAMPLE 1F (2.4 g, 4.63 mmol),
N.sup.1,N.sup.2-dimethylethane-1,2-diamine (40.83 g, 0.463 mmol),
CuI (88 g, 0.463 mmol) and K.sub.3PO.sub.4 (983 g, 4.63 mmol) in
DMF (30 mL) was stirred at 60.degree. C. for 1 h by microwave under
N.sub.2 atmosphere. The mixture was cooled to room temperature and
then filtrated through a pad of Celite, and the filtrate was
evaporated under vacuum to give a residue which was purified by
column chromatography to provide the title compound as a white
solid (0.4 g, 15%). LCMS (ESI) m/z: 437, 439 (M, M+2).
Example 1H
methyl
3-(1-(tert-butoxycarbonyl)piperidin-4-yl)-6-fluoro-4H-benzo[4,5]imi-
dazo[1,2-b]pyrazole-8-carboxylate
##STR00051##
A mixture of EXAMPLE 1G (200 g, 0.457 mmol), Pd(OAc).sub.2 (10.27
g, 0.0457 mmol), Pd(dppf)Cl.sub.2 (33.46 g, 0.0457 mmol), Xantphos
(53 g, 0.0914 mmol), DPPP (38 g, 0.0914 mmol), PPh.sub.3 (24 mg,
0.0914 mmol) and Et.sub.3N (232 g, 2.29 mmol) in DMF (40 mL) and
MeOH (20 mL) was stirred at 120.degree. C. for 12 h under CO
atmosphere (3 MPa). The mixture was cooled to room temperature and
then filtrated through a pad of Celite. The filtrate was evaporated
to give the residue which was purified by column chromatography to
provide the title compound as a white solid (100 g, 52%). LCMS
(ESI) m/z: 417 (M+1).
Example 1I
tert-butyl
4-(8-carbamoyl-6-fluoro-4H-benzo[4,5]imidazo[1,2-b]pyrazol-3-yl-
)piperidine-1-carboxylate
##STR00052##
A mixture of EXAMPLE 1H (100 g, 0.24 mmol) and NH.sub.3-MeOH (30
mL) in DMF (100 mL) was reacted at 120.degree. C. for 16 h in a
closed tube. The mixture was cooled and then removed of solution in
vacuum, and the residue was purified by column chromatography to
provide the title compound as a white solid (70 g, 73%). LCMS (ESI)
m/z: 402 (M+1).
Example 1J
6-fluoro-3-(piperidin-4-yl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxam-
ide
##STR00053##
A mixed solution of EXAMPLE 1I (70 g, 0.174 mmol) in DCM (3 mL) and
TFA (1 mL) was stirred at 15.degree. C. for 1 h, and removed of
solution in vacuum. The residue was purified by prep-HPLC to
provide the title compound (25 g, 49%). .sup.1H NMR (400 MHz,
METHANOL-d4) .delta. ppm 1.93-1.96 (m, 2H), 2.37-2.36 (d, 2H),
3.09-3.22 (m, 3H), 3.31-3.53 (t, 2H), 7.37-7.39 (m, 1H), 7.68-7.74
(m, 2H). LCMS (ESI) m/z: 302 (M+1).
Example 2
3-(1-ethylpiperidin-4-yl)-6-fluoro-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-c-
arboxamide
##STR00054##
A mixture of EXAMPLE 1J (750 g, 2.49 mmol) and acetaldehyde (1.1 g,
24.9 mmol) in MeOH (15 mL) was stirred at 50.degree. C. for 0.5 h.
Thereafter, NaCNBH.sub.3 (3.13 g, 49.8 mmol) was added thereto. The
resulting mixture was stirred at 50.degree. C. for 16 h. After
removal of solution in vacuum, the residue was purified by column
chromatography to provide the title compound as a white solid.
(563.1 g, 69%). .sup.1H NMR (400 MHz, METHANOL-d4) .delta. ppm
1.31-1.34 (t, 3H), 1.94-1.97 (m, 2H), 2.27-2.31 (d, 2H), 2.82 (t,
2H), 2.97-3.02 (m, 3H), 3.47-3.48 (d, 2H), 7.34-7.37 (m, 1H),
7.67-7.72 (m, 2H). LCMS (ESI) m/z: 330 (M+1).
Example 3
6-fluoro-3-(1-(2-fluoroethyl)piperidin-4-yl)-4H-benzo[4,5]imidazo[1,2-b]py-
razole-8-carboxamide
##STR00055##
A mixture of EXAMPLE 1J (112 g, 0.372 mmol),
1-bromo-2-methoxyethane (71 g, 0.558 mmol) and potassium carbonate
(154 g, 1.116 mmol) in acetonitrile (20 mL) was stirred at
40.degree. C. for 16 hours. The mixture was cooled and filtrated,
and the filtrate was evaporated under vacuum to give a residue
which was purified by prep-HPLC to provide the title compound (4.6
g, 3.6%). .sup.1H NMR (400 MHz, METHANOL-d.sub.4) ppm 1.94-2.15 (m,
2H), 2.17-2.37 (m, 2H), 2.86-3.07 (m, 3H), 3.27-3.32 (m, 1H),
3.35-3.39 (m, 1H), 3.46-3.61 (m, 2H), 4.71-4.80 (m, 1H), 4.89 (br.
s., 1H), 7.28-7.41 (m, 1H), 7.60-7.76 (m, 2H), 8.24-8.69 (m, 1H).
LCMS (ESI) m/z: 348 (M+1).
Example 4
3-(1-cyclopropylpiperidin-4-yl)-6-fluoro-4H-benzo[4,5]imidazo[1,2-b]pyrazo-
le-8-carboxamide
##STR00056##
A mixture of (1-ethoxycyclopropoxy)trimethylsilane (115 g, 0.663
mmol), EXAMPLE 1J (40 g, 0.133 mmol), HOAc (79 g, 1.33 mmol) and
NaCNBH.sub.3 (83 g, 1.33 mmol) in MeOH (10 mL) was stirred at
66.degree. C. for 7 h. The mixture was cooled and then removed of
solution in vacuum, and the residue was purified by prep-HPLC to
provide the title compound (19.6 g, 43%). .sup.1H NMR (400 MHz,
METHANOL-d4) .delta. ppm 0.70-0.79 (m, 4H), 1.84-1.92 (m, 2H),
2.18-2.28 (t, 3H), 2.85-2.94 (m, 3H), 3.42-3.45 (d, 2H), 7.33-7.35
(m, 1H), 7.65-7.68 (m, 2H), 8.395 (s, 1H). LCMS (ESI) m/z: 342
(M+1).
Example 5
3-(1-(cyclopropylmethyl)piperidin-4-yl)-6-fluoro-4H-benzo[4,5]imidazo[1,2--
b]pyrazole-8-carboxamide
##STR00057##
A mixture of EXAMPLE 1J (12 g, 0.04 mmol), cyclopropanecarbaldehyde
(5.58 g, 0.08 mmol) and NaCNBH.sub.3 (50 g, 0.8 mmol) in MeOH (2
mL) was stirred at 10.degree. C. for 16 h. Thereafter,
tetraisopropoxytitanium (17 g, 0.06 mmol) was added thereto and
continuously stirred for 1 hour. After removal of solution in
vacuum, the residue was purified by prep-HPLC to provide the title
compound (5.2 g, 37%). .sup.1H NMR (400 MHz, METHANOL-d4) ppm
0.40-0.44 (m, 2H), 0.75-0.79 (m, 1H), 1.12-1.13 (m, 1H), 2.04 (s,
2H), 2.32-2.36 (d, 2H), 2.9-3.12 (m, 5H), 3.68 (s, 2H), 7.36-7.39
(m, 1H), 7.68-7.73 (m, 2H), 8.50 (s, 1H). LCMS (ESI) m/z: 356
(M+1).
Example 6
6-fluoro-3-(1-(2-hydroxy-2-methylpropyl)piperidin-4-yl)-4H-benzo[4,5]imida-
zo[1,2-b]pyrazole-8-carboxamide
##STR00058##
Example 6A
tert-butyl
4-(4-benzyl-8-carbamoyl-6-fluoro-4H-benzo[4,5]imidazo[1,2-b]pyr-
azol-3-yl)piperidine-1-carboxylate
##STR00059##
A mixture of EXAMPLE 1I (100 g, 0.25 mmol), (bromomethyl)benzene
(127 g, 0.748 mmol) and potassium carbonate (103 g, 0.748 mmol) in
acetonitrile (4 mL) was stirred at 60.degree. C. for 4 hours. The
mixture was cooled and filtered and the filtrate was evaporated
under vacuum to give a residue which was purified by silica gel
chromatography to provide the title compound (112.6 g, 91.8%). LCMS
(ESI) m/z: 492 (M+1).
Example 6B
4-benzyl-6-fluoro-3-(piperidin-4-yl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-
-carboxamide
##STR00060##
A mixture solution of EXAMPLE 6A (112.6 g, 0.229 mmol) in DCM (9
mL) TFA (3 mL) was stirred at 12.degree. C. for 2 hours. After
removal of solution in vacuum, the title compound (115 g, 100%) was
provided as yellow solid which could be used directly in the next
step without further purification. LCMS (ESI) m/z: 392 (M+1).
Example 6C
4-benzyl-6-fluoro-3-(1-(2-hydroxy-2-methylpropyl)piperidin-4-yl)-4H-benzo[-
4,5]imidazo[1,2-b]pyrazole-8-carboxamide
##STR00061##
A mixture of EXAMPLE 6B (115 g, 0.229 mmol), 2,2-dimethyloxirane
(50 g, 0.690 mmol) and Et.sub.3N (116 g, 1.15 mmol) in ethanol (5
ml) was heated at 120.degree. C. under microwave for 1 hour. The
mixture was cooled and removed of solution in vacuum, and then the
residue was purified by silica gel chromatography to provide the
title compound. LCMS (ESI) m/z: 464 (M+1).
Example 6D
6-fluoro-3-(1-(2-hydroxy-2-methylpropyl)piperidin-4-yl)-4H-benzo[4,5]imida-
zo[1,2-b]pyrazole-8-carboxamide
##STR00062##
A mixture of EXAMPLE 6C (32 g, 0.069 mmol) and Pd/C (25 mg) in
Methanol (30 mL) was hydrogenated at 50.degree. C. for 4 hours
under H.sub.2 (1 atm). The mixture was cooled and filtered, and the
filtrate was evaporated under vacuum. Thereafter the residue was
purified by prep-HPLC to provide the title compound (8.2 g, 32.2%).
.sup.1H NMR (400 MHz, METHANOL-d.sub.4) ppm 1.38 (s, 6H), 2.10-2.30
(m, 4H), 3.12 (s, 5H), 3.57-3.73 (m, 2H), 7.29-7.39 (m, 1H),
7.61-7.69 (m, 1H), 7.69-7.75 (m, 1H), 8.54 (br. s., 1H). LCMS (ESI)
m/z: 374 (M+1).
Example 7
6-fluoro-3-(1-(2-fluoro-2-methylpropyl)piperidin-4-yl)-4H-benzo[4,5]imidaz-
o[1,2-b]pyrazole-8-carboxamide
##STR00063##
Example 7A
4-benzyl-6-fluoro-3-(1-(2-fluoro-2-methylpropyl)piperidin-4-yl)-4H-benzo[4-
,5]imidazo[1,2-b]pyrazole-8-carboxamide
##STR00064##
To a mixture of EXAMPLE 6C (32 g, 0.069 mmol) in DCM (10 mL) was
added dropwise a solution of DAST (33 g, 0.207 mmol) in DCM (2 mL)
at 0.degree. C. under N.sub.2 atmosphere. After the dropwise
addition was completed, the mixture was stirred at 17.degree. C.
for 16 h, and then quenched with saturated sodium bicarbonate
solution (10 mL). The aqueous layer was extracted with EtOAc (10
mL.times.2). The combined organic layers were dried over
Na.sub.2SO.sub.4, filtered and evaporated. The residue was purified
by silica gel chromatography to provide the title compound (27 g,
84.4%). LCMS (ESI) m/z: 466 (M+1).
Example 7B
6-fluoro-3-(1-(2-fluoro-2-methylpropyl)piperidin-4-yl)-4H-benzo[4,5]imidaz-
o[1,2-b]pyrazole-8-carboxamide
##STR00065##
A mixture of EXAMPLE 7A (27 g, 0.058 mmol) and Pd/C (30 mg) in
Methanol (20 mL) was hydrogenated at 45.degree. C. for 16 hours
under H.sub.2 (1 atm). The mixture was cooled and filtered and the
filtrate was evaporated. The residue was purified by prep-HPLC to
provide the title compound (2.1 g, 10%). .sup.1H NMR (400 MHz,
METHANOL-d.sub.4) ppm 1.42 (s, 3H), 1.48 (s, 3H), 1.90-2.03 (m,
2H), 2.04-2.16 (m, 2H), 2.51-2.67 (m, 2H), 2.72-2.90 (m, 3H),
3.23-3.31 (m, 2H), 7.32-7.41 (m, 1H), 7.63-7.75 (m, 2H), 8.27-8.59
(m, 1H). LCMS (ESI) m/z: 376 (M+1)
Example 8
3-(1-(cyclopropylcarbonyl)piperidin-4-yl)-6-fluoro-4H-benzo[4,5]imidazo[1,-
2-b]pyrazole-8-carboxamide
##STR00066##
A mixture of EXAMPLE 1J (52 g, 0.125 mmol), cyclopropanecarboxylic
acid (13 g, 0.150 mmol), Et.sub.3N (50.5 g, 0.5 mmol) and HATU
(47.5 g, 0.125 mmol) in acetonitrile (5 mL) was stirred at
50.degree. C. for 3 hours. After the mixture was cooled and removed
of solution in vacuum, the residue was purified by prep-HPLC to
provide the title compound (12.7 g, 27.3%). LCMS: 370 [M+1].
.sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 0.72 (d, J=7.53 Hz, 4H),
1.42-1.69 (m, 2H), 1.88-2.07 (m, 3H), 2.65-2.77 (m, 1H), 2.86-2.98
(m, 1H), 3.14-3.29 (m, 1H), 4.26-4.50 (m, 2H), 7.43-7.50 (m, 1H),
7.51-7.59 (m, 1H), 7.76 (s, 1H). LCMS (ESI) m/z: 370 (M+1).
Example 9
6-fluoro-3-(1-methy
piperidin-4-yl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide
##STR00067##
This example was prepared as the method described in Example 2.
.sup.1H NMR (400 MHz, METHANOL-d4) .delta. ppm 1.98-2.01 (d, 2H),
2.29-2.31 (d, 2H), 2.83 (s, 1H), 3.01-3.04 (d, 2H), 3.48 (d, 2H),
7.36-7.39 (m, 1H), 7.68-7.73 (m, 2H), 8.49 (s, 1H). LCMS (ESI) m/z:
316 (M+1).
Example 10
6-fluoro-3-(1-isopropylpiperidin-4-yl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole-
-8-carboxamide
##STR00068##
This example was prepared as the method described in Example 2.
.sup.1H NMR (400 MHz, METHANOL-d4) .delta. ppm 1.38-1.40 (d, 6H),
2.02-2.05 (d, 2H), 2.36-2.40 (d, 2H), 3.06 (m, 1H), 3.19-3.22 (t,
2H), 3.51-3.55 (m, 3H), 7.35-7.38 (m, 1H), 7.66-7.72 (m, 2H), 8.51
(s, 1H). LCMS (ESI) m/z: 344 (M+1).
Example 11
6-fluoro-3-(1-(oxetan-3-yl)piperidin-4-yl)-4H-benzo[4,5]imidazo[1,2-b]pyra-
zole-8-carboxamide
##STR00069##
This example was prepared as the method described in Example 2.
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 1.66-1.79 (m, 2H),
1.82-1.99 (m, 4H), 2.58-2.69 (m, 1H), 2.70-2.81 (m, 2H), 3.36-3.45
(m, 1H), 4.45 (s, 2H), 4.51-4.58 (m, 2H), 7.36-7.44 (m, 1H),
7.45-7.53 (m, 1H), 7.65-7.75 (m, 1H). LCMS (ESI) m/z: 358
(M+1).
Example 12
6-fluoro-3-(1-propylpiperidin-4-yl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8--
carboxamide
##STR00070##
This example was prepared as the method described in Example 2.
.sup.1H-NMR (400 MHz, METHANOL-d4) .delta. ppm 1.02-1.06 (t, 3H),
1.76-1.82 (m, 2H), 2.00-2.03 (d, 2H), 2.31-2.34 (d, 2H), 3.01-3.05
(m, 5H), 3.57-3.58 (d, 2H), 7.36-7.39 (m, 1H), 7.68-7.73 (m, 2H),
8.51 (s, 1H). LCMS (ESI) m/z: 344 (M+1).
Example 13
3-(1-(2-aminoethyl)piperidin-4-yl)-6-fluoro-4H-benzo[4,5]imidazo[1,2-b]pyr-
azole-8-carboxamide
##STR00071##
This example was prepared as the method described in Example 2.
.sup.1H NMR (400 MHz, METHANOL-d.sub.4) .delta. ppm 1.80-1.98 (m,
2H), 2.06-2.17 (m, 2H), 2.30-2.46 (m, 2H), 2.68-2.85 (m, 3H),
3.05-3.19 (m, 4H), 7.30-7.38 (m, 1H), 7.69 (br. s., 2H), 8.28-8.67
(m, 1H). LCMS (ESI) m/z: 345 (M+1).
Example 14
3-(1-(2-(dimethylamino)ethyl)piperidin-4-yl)-6-fluoro-4H-benzo[4,5]imidazo-
[1,2-b]pyrazole-8-carboxamide
##STR00072##
This example was prepared as the method described in Example 2.
.sup.1H NMR (400 MHz, METHANOL-d.sub.4) .delta. ppm 1.83-1.98 (m,
2H), 2.05-2.18 (m, 2H), 2.36-2.48 (m, 2H), 2.68 (s, 6H), 2.80 (t,
J=6.46 Hz, 3H), 2.97-3.07 (m, 2H), 3.11-3.25 (m, 2H), 7.25-7.40 (m,
1H), 7.57-7.75 (m, 2H). LCMS (ESI) m/z: 373 (M+1).
Example 15
6-fluoro-3-(1-(2-methoxyethyl)piperidin-4-yl)-4H-benzo[4,5]imidazo[1,2-b]p-
yrazole-8-carboxamide
##STR00073##
This example was prepared as the method described in Example 3.
.sup.1H NMR (400 MHz, METHANOL-d4) ppm 2.00-2.18 (m, 2H), 2.22-2.38
(m, 2H), 2.94-3.08 (m, 1H), 3.08-3.22 (m, 2H), 3.33-3.38 (m, 2H),
3.44 (s, 3H), 3.56-3.70 (m, 2H), 3.71-3.82 (m, 2H), 7.19-7.38 (m,
1H), 7.53-7.64 (m, 1H), 7.68 (s, 1H), 8.42-8.66 (m, 1H). LCMS (ESI)
m/z: 360 (M+1).
Example 16
6-fluoro-3-(1-(2-hydroxyethyl)piperidin-4-yl)-4H-benzo[4,5]imidazo[1,2-b]p-
yrazole-8-carboxamide
##STR00074##
This example was prepared as the method described in Example 3.
.sup.1H NMR (400 MHz, METHANOL-d.sub.4) .delta. ppm 2.04-2.20 (m,
2H), 2.25-2.37 (m, 2H), 2.98-3.10 (m, 1H), 3.12-3.24 (m, 2H),
3.25-3.31 (m, 2H), 3.62-3.75 (m, 2H), 3.89-3.99 (m, 2H), 7.25-7.38
(m, 1H), 7.57-7.66 (m, 1H), 7.69 (s, 1H), 8.50-8.62 (m, 1H). LCMS
(ESI) m/z: 346 (M+1).
Example 17
3-(1-ethylpiperidin-3-yl)-6-fluoro-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-c-
arboxamide
##STR00075##
This example was prepared as described in Examples 1 and 2,
substituting tert-butyl 3-(hydroxymethyl)piperidine-1-carboxylate
for tert-butyl 4-(hydroxymethyl)piperidine-1-carboxylate.
.sup.1H-NMR (MeOD, 400 MHz) .delta.: 1.38 (t, 3H), 1.85-2.00 (m,
2H), 2.13-2.26 (m, 2H), 2.94-3.03 (m, 2H), 3.21-3.24 (m, 3H),
3.59-3.73 (m, 2H), 7.37-7.39 (dd, 1H), 7.66-7.69 (dd, 1H), 7.76 (s,
1H), 8.52 (bs, 1H). LCMS (ESI) m/z: 331 (M+1).
Example 18
3-(1-ethylazepan-4-yl)-6-fluoro-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carb-
oxamide
##STR00076##
Example 18A
1-tert-butyl 4-ethyl 5-oxoazepane-1,4-dicarboxylate
##STR00077##
To a solution of tert-butyl 4-oxopiperidine-1-carboxylate (50 g,
251 mmol) and BF.sub.3-Et.sub.2O (49.86 g, 351 mmol) in THF (500
ml) was added dropwise ethyl 2-diazo (40.09 g, 351 mmol) at
-40.degree. C. under N.sub.2 atmosphere. After the dropwise
addition was completed, the mixture was stirred at -40.degree. C.
for 2 h and then warmed to 15.degree. C. and stirred for 16 h.
After the reaction completed, the mixture was quenched with
K.sub.2CO.sub.3 aqueous solution (500 mL). The aqueous layer was
extracted with EtOAc (500 mL.times.2). The combined organic layers
were washed with water, and brine, thereafter dried over
Na.sub.2SO.sub.4, filtered and evaporated. The residue was purified
by column chromatograph on silica gel to provide the title compound
(45 g, yield: 63%). LCMS (ESI) m/z: 286 (M+1).
Example 18B
1-tert-butyl 4-ethyl 5-hydroxyazepane-1,4-dicarboxylate
##STR00078##
To a solution of EXAMPLE 18A (45 g, 157.7 mmol) in MeOH (420 ml)
was added NaBH.sub.4 (7.16 g, 189 mmol) in portions at 0.degree. C.
After stirring at 0.degree. C. for 1 h, the resultant mixture was
quenched with water (400 mL) and the aqueous phase was extracted
with EtOAc (400 mL.times.2). The combined organic layers were
washed with water, brine, dried over Na.sub.2SO.sub.4, filtered and
evaporated. The residue was purified by column chromatograph on
silica gel to provide the title compound (22.3 g, yield: 49%). LCMS
(ESI) m/z: 288 (M+1).
Example 18C
1-tert-butyl 4-ethyl
2,3,6,7-tetrahydro-1H-azepine-1,4-dicarboxylate
##STR00079##
To a solution of EXAMPLE 18B (21 g, 73 mmol), DBU (22 g, 146 mmol)
in toluene (200 mL) was added dropwise MsCl (14.56 g, 128 mmol).
After the dropwise addition was completed, the mixture was stirred
at 110.degree. C. for 2 h, and cooled to room temperature, and then
water (200 mL) was added to quench. The aqueous layer was extracted
with EtOAc (200 mL.times.2). The combined organic layers were
washed with water, brine, dried over Na.sub.2SO.sub.4, filtered and
evaporated. The residue was purified by column chromatograph on
silica gel to provide the title compound (13 g, yield: 66%). LCMS
(ESI) m/z: 270 (M+1).
Example 18D
1-tert-butyl 4-methyl azepane-1,4-dicarboxylate
##STR00080##
A mixture of EXAMPLE 18C (13 g, 48.27 mmol) and Pd/C (1 g) in MeOH
(130 mL) was hydrogenated at 15.degree. C. for 16 h under H.sub.2
(1 atm). The mixture was filtered and the filtrate was evaporated
to provide the title compound which could be used directly in the
next step without further purification (10.7 g, yield: 82%). LCMS
(ESI) m/z: 258 (M+1).
Example 18E
tert-butyl 4-(hydroxymethyl)azepane-1-carboxylate
##STR00081##
To a solution of EXAMPLE 18D (10.7 g, 39 mmol) in THF (200 mL) was
added LiAlH.sub.4 (1.48 g, 39 mmol) in portions at 0.degree. C.
After stirring at 0.degree. C. for 30 mins, the resultant mixture
was quenched with water (10 mL), 15% aq NaOH (10 mL), water (30
mL). The mixture was filtered and the filtrate was evaporated. The
residue was purified by column chromatograph on silica gel to
provide the title compound (7 g, yield: 77%). LCMS (ESI) m/z: 230
(M+1).
Example 18F
3-(1-ethylazepan-4-yl)-6-fluoro-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carb-
oxamide
##STR00082##
This example was prepared as described in Examples 1 and 2,
substituting tert-butyl 4-(hydroxymethyl)azepane-1-carboxylate for
tert-butyl 4-(hydroxymethyl)piperidine-1-carboxylate. .sup.1H-NMR
(MeOD, 400 MHz) .delta.: 1.38-1.42 (t, 3H), 1.93-1.96 (m, 2H),
1.99-2.12 (m, 2H), 2.32-2.34 (m, 2H), 3.15-3.30 (m, 1H), 3.32-3.33
(m, 2H), 3.33-3.53 (m, 4H), 7.38-7.40 (dd, 1H), 7.69-7.73 (dd, 1H),
7.74 (s, 1H), 8.50 (bs, 1H). LCMS (ESI) m/z: 344 (M+1).
Example 19
6-fluoro-3-(1-methylazepan-4-yl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-car-
boxamide
##STR00083##
This example was prepared as the method described in Example 18.
.sup.1H-NMR (MeOD, 400 MHz) .delta.: 1.95-2.10 (m, 3H), 2.26-2.35
(m, 3H), 2.96 (s, 1H), 3.14-3.17 (m, 1H), 3.36-3.49 (m, 4H),
7.38-7.40 (dd, 1H), 7.69-7.72 (dd, 1H), 7.74 (s, 1H), 8.47 (bs,
1H). LCMS (ESI) m/z: 330 (M+1).
Example 20
6-fluoro-3-(1-methylpyrrolidin-3-yl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-
-carboxamide
##STR00084##
This example was prepared as described in Examples 1 and 2,
substituting tert-butyl 3-(hydroxymethyl)pyrrolidine-1-carboxylate
for tert-butyl 4-(hydroxymethyl)piperidine-1-carboxylate.
.sup.1H-NMR (MeOD, 400 MHz) .delta.: 2.29-2.35 (m, 1H), 2.59-2.62
(m, 1H), 2.99 (s, 3H), 3.32-3.36 (m, 1H), 3.53-3.55 (m, 2H),
3.76-3.81 (m, 2H), 7.40-7.42 (dd, 1H), 7.70-7.73 (dd, 1H), 7.80 (s,
1H), 8.50 (bs, 1H). LCMS (ESI) m/z: 302 (M+1).
Example 21
3-(1-ethylpyrrolidin-3-yl)-6-fluoro-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8--
carboxamide
##STR00085##
This example was prepared as described in Example 20, substituting
tert-butyl 3-(hydroxymethyl)pyrrolidine-1-carboxylate for
tert-butyl 4-(hydroxymethyl)piperidine-1-carboxylate. .sup.1H-NMR
(MeOD, 400 MHz) .delta.: 2.29-2.35 (m, 1H), 2.59-2.62 (m, 1H), 2.99
(s, 3H), 3.32-3.36 (m, 1H), 3.53-3.55 (m, 2H), 3.76-3.81 (m, 2H),
7.40-7.42 (dd, 1H), 7.70-7.73 (dd, 1H), 7.80 (s, 1H), 8.50 (bs,
1H). LCMS (ESI) m/z: 316 (M+1).
Example 22
6-fluoro-3-(1-isopropylpyrrolidin-3-yl)-4H-benzo[4,5]imidazo[1,2-b]pyrazol-
e-8-carboxamide
##STR00086##
This example was prepared as described in Example 20, substituting
tert-butyl 3-(hydroxymethyl)pyrrolidine-1-carboxylate for
tert-butyl 4-(hydroxymethyl)piperidine-1-carboxylate. .sup.1H-NMR
(MeOD, 400 MHz) .delta.: 1.42-1.44 (d, 6H), 2.25-2.31 (m, 1H),
2.57-2.60 (m, 1H), 3.32-3.33 (m, 1H), 3.44-3.55 (m, 3H), 3.68-3.71
(m, 1H), 7.41-7.43 (dd, 1H), 7.71-7.74 (dd, 1H), 7.82 (s, 1H), 8.55
(bs, 1H). LCMS (ESI) m/z: 330 (M+1).
Example 23
6-fluoro-3-(pyrrolidin-2-yl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxa-
mide
##STR00087##
This example was prepared as described in Example 1, substituting
tert-butyl 2-(hydroxymethyl)pyrrolidine-1-carboxylate for
tert-butyl 4-(hydroxymethyl)piperidine-1-carboxylate. .sup.1H-NMR
(400 MHz, MethanoL-d.sub.4) .delta. ppm 2.17-2.31 (m, 1H),
2.33-2.51 (m, 2H), 2.52-2.67 (m, 1H), 3.48 (t, J=7.28 Hz, 2H), 7.40
(dd, J=8.03, 2.26 Hz, 1H), 7.65 (dd, J=10.79, 2.26 Hz, 1H), 7.94
(s, 1H), 8.55 (br. s., 1H). LCMS (ESI) m/z: 288 (M+1).
Example 24
6-fluoro-3-(1-propylpyrrolidin-2-yl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-
-carboxamide
##STR00088##
This example was prepared as described in Example 2, substituting
tert-butyl 2-(hydroxymethyl)pyrrolidine-1-carboxylate for
tert-butyl 4-(hydroxymethyl)piperidine-1-carboxylate. .sup.1H-NMR
(400 MHz, MethanoL-d.sub.4) .delta. ppm 0.93 (t, J=7.34 Hz, 3H),
1.54-1.79 (m, 2H), 2.23 (d, J=5.02 Hz, 2H), 2.37-2.53 (m, 2H), 2.76
(br. s., 1H), 3.05 (br. s., 2H), 3.65 (br. s., 1H), 4.31 (br. s.,
1H), 7.44 (dd, J=8.09, 2.32 Hz, 1H), 7.73 (dd, J=10.92, 2.38 Hz,
1H), 7.94 (s, 1H), 8.54 (br. s., 1H). LCMS (ESI) m/z: 330
(M+1).
Example 25
6-fluoro-3-(1-methylpyrrolidin-2-yl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-
-carboxamide
##STR00089##
This example was prepared as described in Example 2, substituting
tert-butyl 2-(hydroxymethyl)pyrrolidine-1-carboxylate for
tert-butyl 4-(hydroxymethyl)piperidine-1-carboxylate. .sup.1H-NMR
(400 MHz, MethanoL-d.sub.4) .delta. ppm 2.25-2.41 (m, 2H),
2.47-2.67 (m, 2H), 2.82 (s, 3H), 3.23-3.30 (m, 1H), 3.66-3.79 (m,
1H), 4.50-4.58 (m, 1H), 7.43 (dd, J=8.16, 2.51 Hz, 1H), 7.64 (dd,
J=10.73, 2.57 Hz, 1H), 7.95-8.02 (m, 1H), 8.52 (br. s., 1H). LCMS
(ESI) m/z: 302 (M+1).
Example 26
3-(1-ethylpyrrolidin-2-yl)-6-fluoro-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8--
carboxamide
##STR00090##
This example was prepared as described in Example 2, substituting
tert-butyl 2-(hydroxymethyl)pyrrolidine-1-carboxylate for
tert-butyl 4-(hydroxymethyl)piperidine-1-carboxylate. .sup.1H-NMR
(400 MHz, MethanoL-d.sub.4) .delta. ppm 1.30 (t, J=7.28 Hz, 3H),
2.26-2.37 (m, 2H), 2.46-2.61 (m, 2H), 2.98-3.09 (m, 1H), 3.25 (d,
J=10.29 Hz, 2H), 3.68-3.80 (m, 1H), 4.55 (t, J=8.78 Hz, 1H), 7.42
(dd, J=8.16, 2.26 Hz, 1H), 7.64 (dd, J=10.73, 2.32 Hz, 1H), 7.97
(s, 1H), 8.54 (br. s., 1H). LCMS (ESI) m/z: 316 (M+1).
Example 27
3-(1-ethylpiperidin-4-yl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamid-
e
##STR00091##
This example was prepared as described in Example 1, substituting
(2,6-dibromophenyl)hydrazine for
(2,6-dibromo-4-fluorophenyl)hydrazine. .sup.1H-NMR (400 MHz,
METHANOL-d4) .delta. ppm 1.16-1.20 (t, 3H), 1.84-1.87 (m, 2H),
2.07-2.11 (d, 2H), 2.16-2.19 (d, 2H), 2.51-2.56 (q, 2H), 2.70-2.75
(m, 1H), 3.11-3.13 (d, 2H), 7.40-7.44 (t, 1H), 7.61-7.63 (m, 1H),
7.70 (s, 1H), 7.99-8.02 (m, 1H). LCMS (ESI) m/z: 312 (M+1).
Example 28
6-fluoro-3-(3-methyl-3-azabicyclo[3.1.0]hexan-1-yl)-4H-benzo[4,5]imidazo[1-
,2-b]pyrazole-8-carboxamide
##STR00092##
Example 28A
ethyl 1-benzyl-2,5-dihydro-1H-pyrrole-3-carboxylate
##STR00093##
To a solution of
N-benzyl-1-methoxy-N-((trimethylsilyl)methyl)methanamine (4.5 g, 61
mmol) and ethyl propiolate (5.0 g, 51 mmol) in DCM (150 mL) was
added dropwise Et.sub.3N (0.4 mL, 5.2 mmol) at 0.degree. C. After
the dropwise addition was completed, the reaction mixture was
stirred at 0.degree. C. for 1 h and warmed to 20.degree. C. and
stirred for 24 h, and then quenched with saturated NaHCO.sub.3 (100
mL).
The aqueous phase was extracted with DCM (250 mL.times.2). The
combined organic layers were washed with brine (150 mL.times.2) and
dried over Na.sub.2SO.sub.4, filtered and evaporated. The residue
was purified by column chromatograph to provide the title compound
(10 g, yield: 80%) as a yellow oil. LCMS (ESI) m/z: 232 (M+1).
Example 28B
ethyl 3-benzyl-3-azabicyclo[3.1.0]hexane-1-carboxylate
##STR00094##
To a mixture of (CH.sub.3).sub.3SOI (21.5 g, 97.7 mmol) in DMSO
(150 mL) was added portion wise 60% NaH (3.5 g, 87.5 mmol) at
0.degree. C.-5.degree. C. under N.sub.2 atmosphere. After the
addition was completed, the mixture was stirred at 19.degree. C.
for 2 h, and thereafter a solution of EXAMPLE 28A (9 g, 38.9 mmol)
was added thereto portionwise at 0.degree. C.-5.degree. C. The
mixed reaction solution was stirred at 19.degree. C. for 15 h, and
then quenched with saturated NaHCO.sub.3 (300 mL). The aqueous
phase was extracted with DCM (500 mL.times.2). The combined organic
layers were washed with brine (200 mL.times.2) and dried over
Na.sub.2SO.sub.4, filtered and evaporated. The residue was purified
by column chromatograph to provide the title compound (5.4 g,
yield: 32%) as a yellow oil. LCMS (ESI) m/z: 246 (M+1).
Example 28C
3-tert-butyl 1-ethyl
3-azabicyclo[3.1.0]hexane-1,3-dicarboxylate
##STR00095##
A mixture of EXAMPLE 28B (5.4 g, 22 mmol), BOC.sub.2O (10 g, 46
mmol) and 10% Pd/C (600 mg) in MeOH (100 mL) was hydrogenated at
19.degree. C. for 15 h under H.sub.2 (1 atm). The mixture was
filtered and the filtrate was evaporated. The residue was purified
by column chromatograph to provide the title compound (5.3 g,
yield: 94%) as a colorless oil. .sup.1H-NMR (400 MHz, CDCl.sub.3)
.delta. ppm 0.83 (t, J=4.96 Hz, 1H), 1.25 (t, J=7.15 Hz, 3H),
1.39-1.48 (m, 9H), 1.56 (dd, J=8.34, 4.58 Hz, 1H), 1.79 (s, 1H),
1.94-2.10 (m, 1H), 3.41 (dd, J=10.73, 3.45 Hz, 1H), 3.50-3.82 (m,
3H), 4.07-4.19 (m, 2H), 4.25 (d, J=7.15 Hz, 1H), 5.05 (s, 1H), 6.61
(t, J=1.88 Hz, 1H), 7.14 (s, 1H), 7.28-7.38 (m, 1H)
Example 28D
tert-butyl
1-(hydroxymethyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate
##STR00096##
A mixture of EXAMPLE 28C (5.3 g, 20.7 mmol) and 1N LiOH (50 mL, 50
mmol) in THF (25 mL) and MeOH (50 mL) was stirred at 60.degree. C.
for 2 hours. The mixture was cooled to room temperature and
thereafter extracted with EtOAc (100 mL.times.2). The combined
organic layers were washed with water (50 mL.times.2), brine (50
mL.times.2), dried over Na.sub.2SO.sub.4 and evaporated to give the
residue. The residue was dissolved in THF (100 mL), and thereto was
added dropwise 10M BH.sub.3-DMS (10 mL, 100 mmol) at 0.degree. C.
under N.sub.2 atmosphere. After the dropwise addition was
completed, the mixture was stirred at 19.degree. C. for 15 h, and
after completion of the reaction quenched with MeOH (100 mL). The
solution was evaporated under vacuum. The residue was purified by
column chromatograph to provide the title compound (3.5 g, yield:
89%) as a colorless oil. .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta.
ppm 0.51 (br. s., 1H, 0.78 (dd, J=8.09, 5.08 Hz, 1H), 1.37-1.47 (m,
10H), 3.42 (d, J=10.29 Hz, 2H, 3.48-3.78 (m, 4H).
Example 28E
tert-butyl
1-(chloromethyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate
##STR00097##
To a mixture of EXAMPLE 28D (3.5 g, 16.43 mmol), DMAP (200 g, 1.6
mmol) and Et.sub.3N (5 mL, 36.14 mmol) in DCM (100 mL) was added
portionwise TosCl (3.7 g, 19.47 mmol) at 0.degree. C. After being
stirred at 24.degree. C. for 15 h, the mixture was quenched with
water (100 mL). The aqueous layer was extracted with DCM (250
mL.times.2). The combined organic layers were washed with brine,
dried over Na.sub.2SO.sub.4, filtered and evaporated. The residue
was purified by column chromatograph to provide the title compound
(2.6 g, yield: 68%), as a colorless oil. .sup.1H-NMR (400 MHz,
CDCl.sub.3) .delta. ppm 0.68 (t, J=4.64 Hz, 1H), 0.90 (dd, J=8.16,
5.27 Hz, 1H), 1.39-1.55 (m, 10H), 3.36-3.46 (m, 2H), 3.48-3.77 (m,
4H).
Example 28F
tert-butyl
1-(cyanomethyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate
##STR00098##
A mixture of EXAMPLE 28E (2.6 g, 11 mmol), NaCN (1.57 g, 32 mmol)
and KI (1.87 g, 11 mmol) in DMSO (40 mL) was stirred at
100-120.degree. C. for 2 h. After being cooled to room temperature,
the mixture was partitioned between EtOAc (200 mL) and
Na.sub.2CO.sub.3 aqueous solution (120 mL). The aqueous layer was
extracted with EtOAc (100 mL.times.2). The combined organic layers
were washed with brine, dried over Na.sub.2SO.sub.4, filtered and
evaporated. The residue was purified by column chromatograph to
provide the title compound (2.4 g, yield: 96%) as a colorless oil.
.sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. ppm 0.47-0.72 (m, 1H),
0.81-0.96 (m, 1H), 1.34-1.55 (m, 10H), 2.53-2.80 (m, 2H), 3.30 (d,
J=10.54 Hz, 1H), 3.38-3.84 (m, 1H). LCMS (ESI) m/z: 167 (M-55).
Example 28G
tert-butyl
1-(1-cyano-2-(dimethylamino)vinyl)-3-azabicyclo[3.1.0]hexane-3--
carboxylate
##STR00099##
A mixture of 1-tert-butoxy-N,N,N',N'-tetramethylmethanediamine (3.8
g, 21.8 mmol) and EXAMPLE 28F (2.4 g, 10.8 mmol) in DMF (20 mL) was
stirred at 70.degree. C. for about 10 h. After being cooled to room
temperature, the resultant mixture was evaporated off solvent under
vacuum to provide the title compound which could be used directly
in the next step without further purification.
Example 28H
tert-butyl
1-(1-cyano-2-hydroxyvinyl)-3-azabicyclo[3.1.0]hexane-3-carboxyl-
ate
##STR00100##
A solution of EXAMPLE 28G (3.0 g, crude, 10.8 mmol) in a mixture of
THF/HOAc/Water (1/1/1) (45 mL) was stirred at 24.degree. C. for 5
h. After removal of solution in vacuum, the residue was partitioned
between saturated NaHCO.sub.3 (100 mL) and EtOAc (100 mL). The
aqueous phase was extracted with EtOAc (100 mL.times.2). The
combined organic layers were washed with water (100 mL.times.2),
brine (100 mL.times.2), dried over Na.sub.2SO.sub.4, filtered and
evaporated. The residue was purified by column chromatography to
provide the title compound (1.4 g, yield: 52%) as a yellow oil.
LCMS (ESI) m/z: 195 (M-55).
Example 28I
3-(3-azabicyclo[3.1.0]hexan-1-yl)-6-fluoro-4H-benzo[4,5]imidazo[1,2-b]pyra-
zole-8-carboxamide
##STR00101##
This example was prepared as described in EXAMPLES 1E-1J.
Example 28J
6-fluoro-3-(3-methyl-3-azabicyclo[3.1.0]hexan-1-yl)-4H-benzo[4,5]imidazo[1-
,2-b]pyrazole-8-carboxamide
##STR00102##
This example was prepared as the method described in Example 2.
.sup.1H-NMR (400 MHz, MethanoL-d.sub.4) .delta. ppm 1.32 (d, J=6.40
Hz, 2H), 2.05 (td, J=6.37, 3.95 Hz, 1H), 2.93 (s, 3H), 3.47 (d,
J=11.04 Hz, 1H), 3.59 (dd, J=11.11, 3.83 Hz, 1H), 3.67-3.76 (m,
1H), 3.85 (d, J=11.04 Hz, 1H), 7.32 (dd, J=8.16, 2.51 Hz, 1H), 7.58
(dd, J=10.79, 2.51 Hz, 1H), 7.77 (s, 1H), 8.52 (s, 1H). LCMS (ESI)
m/z: 314 (M+1).
Example 29
3-(3-ethyl-3-azabicyclo[3.1.0]hexan-1-yl)-6-fluoro-4H-benzo[4,5]imidazo[1,-
2-b]pyrazole-8-carboxamide
##STR00103##
This example was prepared as the method described in Example 28.
.sup.1H-NMR (400 MHz, MethanoL-d.sub.4) .delta. ppm 1.27-1.37 (m,
5H), 1.95-2.11 (m, 1H), 3.22 (q, J=7.19 Hz, 2H), 3.41 (d, J=10.92
Hz, 1H), 3.48-3.57 (m, 1H), 3.69 (s, 1H), 3.86 (d, J=10.92 Hz, 1H),
7.33 (dd, J=8.16, 2.51 Hz, 1H), 7.64 (dd, J=10.85, 2.57 Hz, 1H),
7.79 (s, 1H), 8.51 (s, 1H). LCMS (ESI) m/z: 328 (M+1).
Example 30
3-(3-cyclobutyl-3-azabicyclo[3.1.0]hexan-1-yl)-6-fluoro-4H-benzo[4,5]imida-
zo[1,2-b]pyrazole-8-carboxamide
##STR00104##
This example was prepared as the method described in Example 28.
.sup.1H-NMR (400 MHz, DMSO-d.sub.6+D.sub.2O) 0.77 (dd, J=7.91, 4.14
Hz, 1H), 1.22 (t, J=4.14 Hz, 1H), 1.51-1.68 (m, 3H), 1.77-1.96 (m,
4H), 2.47 (br. s., 2H), 2.88 (d, J=8.78 Hz, 1H), 2.98-3.13 (m, 2H),
7.44 (dd, J=8.41, 2.51 Hz, 1H), 7.52 (dd, J=10.98, 2.57 Hz, 1H),
7.71 (s, 1H). LCMS (ESI) m/z: 354 (M+1).
Example 31
3-(3-(cyclopropylmethyl)-3-azabicyclo[3.1.0]hexan-1-yl)-6-fluoro-4H-benzo[-
4,5]imidazo[1,2-b]pyrazole-8-carboxamide
##STR00105##
This example was prepared as the method described in Example 28.
.sup.1H NMR (400 MHz, METHANOL-d4) ppm 0.32-0.35 (m, 2H), 0.65-0.68
(m, 2H), 1.06 (m, 1H), 1.16-1.19 (m, 1H), 1.39-1.42 (t, 1H),
1.92-1.94 (m, 1H), 2.84-2.85 (d, 2H), 3.18-3.21 (m, 1H), 3.56-3.59
(d, 2H), 3.73-3.75 (d, 2H), 7.35-7.39 (dd, 1H), 7.68-7.71 (dd, 1H),
7.78 (s, 1H), 8.55 (s, 1H). LCMS (ESI) m/z: 354 (M+1).
Example 32
6-fluoro-3-(3-isopropyl-3-azabicyclo[3.1.0]hexan-1-yl)-4H-benzo[4,5]imidaz-
o[1,2-b]pyrazole-8-carboxamide
##STR00106##
This example was prepared as the method described in Example 28.
.sup.1H-NMR (400 MHz, MethanoL-d.sub.4) 1.25-1.43 (m, 8H),
2.00-2.15 (m, 1H), 3.39 (s, 1H), 3.49 (d, J=11.04 Hz, 1H), 3.62 (d,
J=3.89 Hz, 1H), 3.71 (s, 1H), 3.90 (d, J=10.92 Hz, 1H), 7.29-7.40
(m, 1H), 7.64 (dd, J=10.85, 2.57 Hz, 1H), 7.79 (s, 1H), 8.52 (br.
s., 1H). LCMS (ESI) m/z: 342 (M+1).
Example 33
3-(3-azabicyclo[3.1.0]hexan-6-yl)-6-fluoro-4H-benzo[4,5]imidazo[1,2-b]pyra-
zole-8-carboxamide
##STR00107##
Example 33A
ethyl
5-benzyl-4,6-dioxo-1,3a,4,5,6,6a-hexahydropyrrolo[3,4-c]pyrazole-3-c-
arboxylate
##STR00108##
A mixture of 1-benzyl-1H-pyrrole-2,5-dione (5.0 g, 26.7 mmol) and
2-propionyldiazenecarbaldehyde (2.9 ml, 28.0 mmol) in toluene (30
mL) was stirred at 30.degree. C. for 5 h. After removal of solution
in vacuum, the residue was purified by silica gel chromatography to
provide the title compound (7.67 g, yield 95.4%). LCMS (ESI) m/z:
302 (M+1).
Example 33B
ethyl
3-benzyl-2,4-dioxo-3-azabicyclo[3.1.0]hexane-6-carboxylate
##STR00109##
EXAMPLE 33A (7.67 g, 25.5 mmol) was heated to 190.degree. C. for 1
hour. The residue was purified by chromatography to provide the
title compound (5.353 g, 76.9%) as white solid. LCMS (ESI) m/z: 274
(M+1).
Example 33C
(3-benzyl-3-azabicyclo[3.1.0]hexan-6-yl)methanol
##STR00110##
To a suspension of LiAlH.sub.4 (3.055 g, 80.4 mmol) in THF (50 mL)
was added dropwise a solution of EXAMPLE 33B (5.353 g, 19.6 mmol)
in 30 ml of THF at 0.degree. C. under N.sub.2 atmosphere. After
refluxing for 16 h, the reaction mixture was quenched with
saturated Na.sub.2SO.sub.4 aqueous solution (5 mL). The organic
layer was dried over Na.sub.2SO.sub.4, filtrated and evaporated to
give the residue which was purified by chromatography to provide
the title compound (1.42 g, 35.8%). LCMS (ESI) m/z: 204 (M+1).
Example 33D
tert-butyl
6-(hydroxymethyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate
##STR00111##
A mixture of EXAMPLE 33C (1.42 g, 7.0 mmol), Boc.sub.2O (1.81 g,
8.4 mmol) and 10% Pd/C (200 mg) in methanol (80 mL) was
hydrogenated at 25.degree. C. for 16 h under H.sub.2 (1 atm). The
mixture was filtered and the filtrate was evaporated to give the
residue which was purified by chromatography to provide the title
compound 4 (1.14 g, 76%). LCMS (ESI) m/z: 214 (M+1).
Example 33E
3-(3-azabicyclo[3.1.0]hexan-6-yl)-6-fluoro-4H-benzo[4,5]imidazo[1,2-b]pyra-
zole-8-carboxamide
##STR00112##
This example was prepared as described in Examples 1E-1J. .sup.1H
NMR (400 MHz, METHANOL-d4) ppm 1.86-1.95 (m, 1H), 2.12-2.22 (m,
2H), 3.49-3.65 (m, 4H), 7.34-7.42 (m, 1H), 7.64-7.74 (m, 2H),
8.42-8.61 (m, 1H). LCMS (ESI) m/z: 300 (M+1).
Example 34
3-(3-ethyl-3-azabicyclo[3.1.0]hexan-6-yl)-6-fluoro-4H-benzo[4,5]imidazo[1,-
2-b]pyrazole-8-carboxamide
##STR00113##
This example was prepared as the method described in Example 28.
.sup.1H NMR (400 MHz, METHANOL-d.sub.4) ppm 1.26 (s, 3H), 1.95-2.02
(m, 2H), 2.11-2.18 (m, 1H), 2.85-2.95 (m, 2H), 2.96-3.08 (m, 2H),
3.42-3.58 (m, 2H), 7.30-7.38 (m, 1H), 7.60-7.65 (m, 1H), 7.65-7.70
(m, 1H). LCMS (ESI) m/z: 328 (M+1).
Example 35
3-(8-ethyl-8-azabicyclo[3.2.1]octan-3-yl)-6-fluoro-4H-benzo[4,5]imidazo[1,-
2-b]pyrazole-8-carboxamide
##STR00114##
Example 35A
tert-butyl-3-cyano-8-azabicyclo[3.2.1]octane-8-carboxylate
##STR00115##
To a mixture of tert-butyl
3-oxo-8-azabicyclo[3.2.1]octane-8-carboxylate (10 g, 44.389 mmol)
in DME (300 mL) and EtOH (6.7 mL) was added portionwise t-BuOK (20
g, 177.557 mmol) and TOSMIC (17.33 g, 88.778 mmol) at 0.degree. C.
under N.sub.2 atmosphere. After being stirred at 60.degree. C. for
16 h, the resultant mixture was quenched with water (100 mL). The
aqueous layer was extracted with EtOAc (100 mL.times.2). The
combined organic layers were washed with water, brine, dried over
Na.sub.2SO.sub.4, filtered and evaporated. The residue was purified
by column chromatograph to provide the title compound (6.08 g,
yield: 57.96%) as a white solid. LCMS (ESI) m/z: 327 (M+1).
Example 35B
8-(tert-butoxycarbonyl)-8-azabicyclo[3.2.1]octane-3-carboxylic
acid
##STR00116##
A solution of EXAMPLE 35A (6.58 g, 27.845 mmol) and KOH (9.36 g,
167.069 mmol) in a mixture of EtOH/H.sub.2O (1:1, 200 mL) was
stirred at 80.degree. C. for 4 h. The resultant mixture was diluted
with water (100 mL) and the aqueous phase was adjusted to pH 3-4
with 2 N HCl, and thereafter extracted with EtOAc (100 mL.times.2).
The combined organic layers were washed with water, brine, dried
over Na.sub.2SO.sub.4, filtered and evaporated to provide the title
compound as a white solid which was used directly in the next step
without further purification (6.01 g, yield: 84.53%).
Example 35C
tert-butyl
3-(hydroxymethyl)-8-azabicyclo[3.2.1]octane-8-carboxylate
##STR00117##
To a solution of EXAMPLE 35B (6 g, 23.529 mmol) in THF (60 mL) was
added BH.sub.3-DMS at 0.degree. C. under N.sub.2 atmosphere. After
the mixture was stirred at 25.degree. C. for 16 h, MeOH (100 mL)
was added to quench. The resultant mixture was evaporated, and the
residue was purified by column chromatograph to provide the title
compound (5.2 g, yield: 92.69%). LCMS (ESI) m/z: 242 (M+1).
Example 35D
3-(8-ethyl-8-azabicyclo[3.2.1]octan-3-yl)-6-fluoro-4H-benzo[4,5]imidazo[1,-
2-b]pyrazole-8-carboxamide
##STR00118##
This example was prepared as described in Examples 1E-1J and 2.
.sup.1H-NMR (MeOD, 400 MHz) .delta.: 1.42-1.45 (t, 3H), 2.18-2.36
(m, 8H), 3.16-3.18 (m, 2H), 3.36-3.42 (m, 1H), 4.13 (s, 2H),
7.36-7.37 (dd, 1H), 7.61-7.66 (dd, 1H), 7.68 (s, 1H), 8.62 (bs,
1H). LCMS (ESI) m/z: 356 (M+1).
Example 36
6-fluoro-3-(4-hydroxypyrrolidin-2-yl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole--
8-carboxamide
##STR00119##
Example 36A
1-(tert-butyl) 2-methyl
4-((tert-butyldiphenylsilyl)oxy)pyrrolidine-1,2-dicarboxylate
##STR00120##
To a mixture of 1-tert-butyl 2-methyl
4-hydroxypyrrolidine-1,2-dicarboxylate (2 g, 8.13 mmol), imidazole
(1.1 g, 16.26 mmol) in anhydrous DCM (50 mL) was added portionwise
TBDPSCl (2.68 g, 9.76 mmol) at 0.degree. C. under N.sub.2
atmosphere. After being stirred at 15.degree. C. for 4 hours, the
reaction mixture was washed with water (10 mL.times.2) and dried
over Na.sub.2SO.sub.4, filtered and evaporated to provide the title
compound (3.9 g, yield: 99%) as a colorless oil which could be used
directly in the next step without further purification.
Example 36B
1-(tert-butoxycarbonyl)-4-((tert-butyldiphenylsilyl)oxy)pyrrolidine-2-carb-
oxylic acid
##STR00121##
A mixture of EXAMPLE 36A (3.9 g, 8.1 mmol) and LiOH (1 g, 24.2
mmol) in a mixed solution of H.sub.2O (20 mL), MeOH (5 mL) and THF
(20 mL) was stirred at 15.degree. C. for 16 h. The mixture was
diluted with water (50 mL) and adjusted to pH 4-5 with 1 N HCl, and
the aqueous layer was extracted with EtOAc (50 mL.times.3). The
combined organic layers were washed with brine, dried over
Na.sub.2SO.sub.4, filtered and evaporated to provide the title
compound (3.7 g, yield: 97%) which was used directly in the next
step without further purification.
Example 36C
tert-butyl
4-((tert-butyldiphenylsilyl)oxy)-2-(hydroxymethyl)pyrrolidine-1-
-carboxylate
##STR00122##
To a mixture of EXAMPLE 36B (3.7 g, 7.89 mmol), Et.sub.3N (2.2 g,
15.8 mmol) in THF (100 mL) was added isopropyl carbonochloridate
(1.2 g, 9.5 mmol) at 0.degree. C. under N.sub.2 atmosphere. After
being stirred at 15.degree. C. for 4 h, the mixture was cooled to
0.degree. C. and NaBH.sub.4 (1.2 g, 31.56 mmol) was added thereto.
The reaction mixture was stirred at 15.degree. C. for 64 hours.
After removal of solution in vacuum, the residue was partitioned
between water (50 mL) and DCM (50 mL). The aqueous layer was
extracted with DCM (50 mL.times.2). The combined organic layers
were washed with brine, dried over Na.sub.2SO.sub.4, filtered and
evaporated. The residue was purified by column chromatograph to
provide the title compound (3.5 g, yield: 100%). LCMS (ESI) m/z:
456 (M+1).
Example 36D
tert-butyl
4-((tert-butyldiphenylsilyl)oxy)-2-(8-carbamoyl-6-fluoro-4H-ben-
zo[4,5]imidazo[1,2-b]pyrazol-3-yl) pyrrolidine-1-carboxylate
##STR00123##
This example was prepared as described in Examples 1E-1J. LCMS
(ESI) m/z: 642 (M+1).
Example 36E
6-fluoro-3-(4-hydroxypyrrolidin-2-yl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole--
8-carboxamide
##STR00124##
A mixture of EXAMPLE 36D (50 g, 0.078 mmol) in HBr/HOAc (0.5 mL)
was stirred at 15.degree. C. for 6 hours. The resultant mixture was
evaporated, and the residue was purified by prep-HPLC to provide
the title compound (10 g, yield: 43%). .sup.1H NMR (400 MHz,
DMSO-d.sub.6)=8.36 (br. s., 1H), 8.06-7.86 (m, 1H), 7.53 (d, J=9.9
Hz, 2H), 4.91 (dd, J=6.1, 11.5 Hz, 1H), 4.56 (br. s., 1H), 3.45 (d,
J=8.8 Hz, 1H), 3.06 (d, J=12.7 Hz, 1H), 2.48-2.41 (m, 1H), 2.21
(dd, J=5.8, 13.0 Hz, 1H). LCMS (ESI) m/z: 304 (M+1).
Example 37
3-cyano-6-fluoro-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide
##STR00125##
Example 37A
5-amino-1-(2,6-dibromo-4-fluorophenyl)-1H-pyrazole-4-carbonitrile
##STR00126##
A mixture of EXAMPLE 1D (4 g, 14 mmol) and
2-(ethoxymethylene)malononitrile (2.24 g, 18.31 mmol) in EtOH (30
mL) was stirred at 80.degree. C. for 1.5 h. The mixture was
evaporated under vacuum to provide the title compound (2.8 g, 56%)
which could be used directly in the next step without further
purification.
Example 37B
8-bromo-6-fluoro-4H-benzo[4,5]imidazo[1,2-b]pyrazole-3-carbonitrile
##STR00127##
A mixture of EXAMPLE 37A (2.8 g, 7.78 mmol),
N.sup.1,N.sup.2-dimethylethane-1,2-diamine (68 g, 0.777 mmol), CuI
(148 g, 0.777 mmol) and K.sub.3PO.sub.4 (1.65 g, 7.78 mmol) in DMF
(30 mL) was stirred at 60.degree. C. for 24 h under N.sub.2
atmosphere. The mixture was cooled to room temperature and filtered
and the filtrate was evaporated to give the residue which was
washed with MeOH and water and then dried under vacuum to provide
the title compound (1.7 g, 78%) which was used directly in the next
step without further purification.
Example 37C
methyl
3-cyano-6-fluoro-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxylate
##STR00128##
A solution of EXAMPLE 37B (1 g, 3.58 mmol), Pd(OAc).sub.2 (161 g,
0.72 mmol), Pd(dppf)C.sub.2 (526 g, 0.72 mmol), Xantphos (420 g,
0.72 mmol), DPPP (296 g, 0.72 mmol), PPh.sub.3 (188 g, 0.72 mmol)
and Et.sub.3N (1.8 g, 18 mmol) in DMF (30 mL) and MeOH (10 mL) was
stirred at 120.degree. C. for 12 h under CO atmosphere (3 MPa).
After being cooled to room temperature, the mixture was filtered
and the filtrate was evaporated to give the residue which was
washed with DCM and dried. The resultant title compound (0.5 g,
54%) was used directly in the next step without further
purification.
Example 37D
3-cyano-6-fluoro-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide
##STR00129##
A mixture of EXAMPLE 37C (20 g, 0.077 mmol) and NH.sub.4OH (5 mL)
in DMF (1 mL) and MeOH (1 mL) was stirred at 120.degree. C. for 4
h. After removal of solution in vacuum, the resultant residue was
purified by prep-HPLC to provide the title compound (2.99 g, 16%).
.sup.1H-NMR (400 MHz, MeOD-d4) .delta. ppm 7.52 (dd, J=7.91 Hz,
1H), 7.80 (dd, J=10.67 Hz, 1H), 8.19 (s, 1H). LCMS (ESI) m/z: 244
(M+1).
Example 38
3-cyano-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide
##STR00130##
This example was prepared as described in Example 37. .sup.1H NMR
(400 MHz, D2O) ppm 7.54-7.58 (t, 1H), 7.75-7.77 (d, 1H), 8.10-8.12
(d, 1H), 8.23 (S, 1H). LCMS (ESI) m/z: 226 (M+1).
Example 39
3-(aminomethyl)-6-fluoro-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide
##STR00131##
To a mixture of EXAMPLE 37D (100 g, 0.4 mmol) in DCM (20 mL) and
MeOH (50 mL) was added NiCl.sub.2-6H.sub.2O (200 g, 0.8 mmol) and
NaBH.sub.4 (47 g, 1.2 mmol) in protions. After being stirred at
0.degree. C. for 5 min, the reaction mixture was evaporated to give
the residue which was purified by prep-HPLC to provide the title
compound (45 g, 45%). .sup.1H NMR (400 MHz, D2O) ppm 4.2 (S, 2H),
7.269-7.318 (t, 2H), 7.796 (S, 1H), 8.399 (S, 1H). LCMS (ESI) m/z:
248 (M+1).
Example 40
3-(cyclopropanecarboxamidomethyl)-6-fluoro-4H-benzo[4,5]imidazo[1,2-b]pyra-
zole-8-carboxamide
##STR00132##
A mixture of EXAMPLE 39 (20 g, 0.081 mmol), cyclopropanecarboxylic
acid (8.36 g, 0.098 mmol), HOBt (13.12 g, 0.0979 mmol), EDCl (18.61
g, 0.097 mmol) and Et.sub.3N (25 g, 0.242 mmol) in DMF (5 mL) was
stirred at 30.degree. C. for 6 h. After removal of solution in
vacuum, the residue was purified by prep-HPLC to provide the title
compound (11.9 g, 48%). .sup.1H NMR (400 MHz, DMSO-d6) .cndot. ppm
0.64-0.72 (m, 4H), 1.52-1.57 (m, 1H), 4.25-2.50 (d, 2H), 7.57-7.61
(m, 2H), 7.82 (s, 1H), 8.13 (s, 1H), 8.44-8.46 (t, 1H), 10.46 (s,
1H), 11.93 (br, 1H). LCMS (ESI) m/z: 316 (M+1).
##STR00133##
Example 41
6-fluoro-3-(4-fluorophenyl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxam-
ide
##STR00134##
Example 41A
ethyl
5-amino-1-(2,6-dibromo-4-fluorophenyl)-1H-pyrazole-4-carboxylate
##STR00135##
A mixture of EXAMPLE 1D (5 g, 17.61 mmol) and ethyl
2-cyano-3-ethoxyacrylate (2.98 g, 17.61 mmol) in EtOH (100 mL) was
stirred at 78.degree. C. for 16 h. After removal of solution in
vacuum, the residue was purified by column chromatograph to provide
the title compound (2.7 g, yield: 38%) which could be used directly
in the next step without further purification.
Example 41B
ethyl
8-bromo-6-fluoro-4H-benzo[4,5]imidazo[1,2-b]pyrazole-3-carboxylate
##STR00136##
A mixture of EXAMPLE 41A (2.7 g, 6.63 mmol), CuI (252 g, 1.33
mmol), N.sup.1,N.sup.2-dimethylethane-1,2-diamine (233.9 g, 2.65
mmol) and K.sub.3PO.sub.4 (4.22 g, 19.9 mmol) in DMF (60 mL) was
stirred at 70.degree. C. for 16 hours under N.sub.2 atmosphere.
After being cooled to room temperature, the mixture was filtered
and the solvent was evaporated off under vacuum. The resultant
residue (2.16 g) could be used directly in the next step without
further purification.
Example 41C
8-bromo-6-fluoro-4H-benzo[4,5]imidazo[1,2-b]pyrazole-3-carboxylic
acid
##STR00137##
A mixture of EXAMPLE 41B (2.16 g, 6.62 mmol) and NaOH (1.06 g,
26.49 mmol) in MeOH (40 mL) and H.sub.2O (10 mL) was stirred at
70.degree. C. for 16 h. After evaporation off solvent, the
resultant residue could be used directly in the next step without
further purification.
Example 41D
8-bromo-6-fluoro-4H-benzo[4,5]imidazo[1,2-b]pyrazole
##STR00138##
A solution of EXAMPLE 41C (1.97 g, 6.61 mmol) in a mixture of
concentrate HCl (20 mL) and H.sub.2O (20 mL) was stirred at
80.degree. C. for 16 h. After neutralized with concentrate
NH.sub.4OH, the resultant mixture was filtered. The cake was washed
with MeOH and dried under vacuum. The obtained solid (1.58 g) could
be used directly in the next step without further purification.
Example 41E
8-bromo-6-fluoro-4-((2-(trimethylsilyl)ethoxy)methyl)-4H-benzo[4,5]imidazo-
[1,2-b]pyrazole
##STR00139##
To a solution of NaH (0.746 g, 18.66 mmol) in THF (10 mL) was added
a solution of EXAMPLE 41D (1.58 g, 6.22 mmol) in THF (20 mL) at
0.degree. C. under N.sub.2 atmosphere. The mixture was stirred at
0.degree. C. for 0.5 h, and thereafter SEMCl (1.56 g, 9.33 mmol)
was added thereto. The mixture was stirred at 0.degree. C. for
another 1 h and then quenched with water (20 mL). The aqueous layer
was extracted with DCM (20 mL.times.3). The combined organic layers
were dried over Na.sub.2SO.sub.4, filtered and evaporated. The
residue was purified by column chromatograph to provide the title
compound (0.43 g, yield: 17% for 4 steps). LCMS (ESI) m/z: 384, 386
(M, M+2).
Example 41F
methyl
6-fluoro-4-((2-(trimethylsilyl)ethoxy)methyl)-4H-benzo[4,5]imidazo[-
1,2-b]pyrazole-8-carboxylate
##STR00140##
A mixture of EXAMPLE 41E (0.43 g, 1.12 mmol), Pd(OAc).sub.2 (50 g,
0.233 mmol), Pd(dppf)Cl.sub.2 (164 mg, 0.233 mmol), Xantphos (194
g, 0.335 mmol), DPPP (138 g, 0.335 mmol), PPh.sub.3 (88 g, 0.335
mmol) and Et.sub.3N (566 g, 5.59 mmol) in DMF (10 mL) and MeOH (10
mL) was stirred at 80.degree. C. for 24 h under CO atmosphere (3
atms). After being cooled to room temperature, the mixture was
filtered and the filtrate was evaporated. The residue was purified
by column chromatograph to provide the title compound (0.265 g,
yield: 63%). LCMS (ESI) m/z: 364 (M+1).
Example 41G
methyl
3-bromo-6-fluoro-4-((2-(trimethylsilyl)ethoxy)methyl)-4H-benzo[4,5]-
imidazo[1,2-b]pyrazole-8-carboxylate
##STR00141##
A mixture of EXAMPLE 41F (0.265 g, 729 mmol) and NBS (117 g, 656
mmol) in DCM (20 mL) was stirred at 10.degree. C. for 20 min. After
removal of solution in vacuum, the residue was purified by column
chromatograph to provide the title compound (0.24 g, yield: 75%).
LCMS (ESI) m/z: 442, 444 (M, M+2).
Example 41H
3-bromo-6-fluoro-4-((2-(trimethylsilyl)ethoxy)methyl)-4H-benzo[4,5]imidazo-
[1,2-b]pyrazole-8-carboxylic acid
##STR00142##
A mixture of EXAMPLE 41G (240 g, 0.542 mmol) and NaOH (108 g, 2.71
mmol) in MeOH (6 mL) and H.sub.2O (1.5 mL) was stirred at
60.degree. C. for 0.5 h. After being cooled to room temperature,
the mixture was adjusted to pH 4 with 1 N HCl and the aqueous phase
was extracted with EtOAc (20 mL.times.3). The combined organic
layers were washed with brine, dried over Na.sub.2SO.sub.4 and
evaporated to provide the title compound (196 g, yield: 84%) which
was used directly in the next step without further
purification.
Example 41I
3-bromo-6-fluoro-4-((2-(trimethylsilyl)ethoxy)methyl)-4H-benzo[4,5]imidazo-
[1,2-b]pyrazole-8-carboxamide
##STR00143##
A mixture of EXAMPLE 41H (0.196 g, 0.46 mmol), HATU (0.226 g, 0.595
mmol), (NH.sub.4).sub.2CO.sub.3 (0.439 g, 4.6 mmol) and Et.sub.3N
(0.138 g, 1.37 mmol) in DMF (8 mL) was stirred at 40.degree. C. for
16 h under N.sub.2 atmosphere. After removal of solution in vacuum,
the residue was diluted with water (10 mL). The aqueous layer was
extracted with EtOAc (15 mL.times.3). The combined organic layers
were washed with brine, dried over Na.sub.2SO.sub.4 and evaporated.
The residue was purified by column chromatograph to provide the
title compound (0.125 g, yield: 64%). LCMS (ESI) m/z: 427, 429 (M,
M+2).
Example 41J
6-fluoro-3-(4-fluorophenyl)-4-((2-(trimethylsilyl)ethoxy)methyl)-4H-benzo[-
4,5]imidazo[1,2-b]pyrazole-8-carboxamide
##STR00144##
A mixture of EXAMPLE 41I (50 g, 0.117 mmol), Pd (dppf)Cl.sub.2 (17
g, 0.023 mmol), Na.sub.2CO.sub.3 (31 mg, 0.292 mmol) and
(4-fluorophenyl)boronic acid (24 g, 0.175 mmol) in DMF (3 mL) and
H.sub.2O (0.5 mL) was stirred at 100.degree. C. for 16 h under
N.sub.2 atmosphere. After removal of solution in vacuum, the
residue was diluted with water (10 mL). The aqueous layer was
extracted with EtOAc (10 mL.times.3). The combined organic layers
were washed with brine, dried over Na.sub.2SO.sub.4, filtered and
evaporated. The residue was purified by prep-TLC to provide the
title compound (40 g, yield: 77%). LCMS (ESI) m/z: 443 (M+1).
Example 41K
6-fluoro-3-(4-fluorophenyl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxam-
ide
##STR00145##
A mixture of EXAMPLE 41J (40 g, 0.090 mmol) in TFA (0.5 mL) and DCM
(0.5 mL) was stirred at 10.degree. C. for 5 h. After removal of the
solution in vacuum, to the residue were added MeOH (3 mL) and
K.sub.2CO.sub.3 (0.037 g, 0.271 mmol). The mixture was stirred at
10.degree. C. for 2 h. The mixture was filtered and the solvent was
evaporated off under vacuum. The residue was purified by prep-HPLC
to provide the title compound (6.3 g, yield: 24%). .sup.1H NMR (400
MHz, DMSO-d6) .delta.: 8.32 (s, 1H), 7.67-7.71 (m, 2H), 7.59-7.61
(d, 1H), 7.55-7.57 (d, 1H), 7.22-7.27 (t, 2H). LCMS (ESI) m/z: 313
(M+1).
Example 42
6-fluoro-3-(2-fluoro-4-((methylamino)methyl)phenyl)-4H-benzo[4,5]imidazo[1-
,2-b]pyrazole-8-carboxamide
##STR00146##
Example 42A
1-(4-bromo-3-fluorophenyl)-N-methylmethanamine
##STR00147##
A mixture of 4-bromo-3-fluorobenzaldehyde (2 g, 9.8 mmol) and
methanamine (30-40% in EtOH) (10 mL, 16.7 mmol) in EtOH (10 mL) was
stirred at 75.degree. C. for 15 h. The mixture was cooled to room
temperature, and then added thereto NaBH.sub.4 (745 g, 19.6 mmol)
in one portion and stirred for another 30 min. After removal of
solution in vacuum, the residue was diluted with saturated
NaHCO.sub.3 (20 mL). The aqueous layer was extracted with EtOAc (50
mL.times.3). The combined organic layers were washed with water (50
mL), brine (50 mL), dried over Na.sub.2SO.sub.4, filtered and
evaporated. The residue was purified by column chromatography to
provide the title compound (1.47 g, yield: 74%). LCMS (ESI) m/z:
218, 220 (M, M+2).
Example 42B
tert-butyl (4-bromo-3-fluorobenzyl)(methyl)carbamate
##STR00148##
A mixture of EXAMPLE 42A (1.47 g, 6.77 mmol), Boc.sub.2O (1.77 g,
8.12 mmol) and Et.sub.3N (1.37 g, 13.54 mmol) in DCM (15 mL) was
stirred at 18.degree. C. for 2 h. After removal of solution in
vacuum, the residue was purified by column chromatograph to provide
the title compound (1.83 g, yield: 85%). LCMS (ESI) m/z: 319
(M+1).
Example 42C
tert-butyl(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-
(methyl)carbamate
##STR00149##
A mixture of
4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (1.76
g, 6.92 mmol), EXAMPLE 42B (1.83 g, 5.77 mmol), KOAc (1.13 g, 11.54
mmol) and Pd(dppf)Cl.sub.2 (422 g, 0.577 mmol) in DMSO (15 mL) was
stirred at 80.degree. C. for 15 h under N.sub.2 atmosphere. After
being cooled to room temperature, the mixture was filtered and the
filtrate was diluted with water (20 mL). The aqueous layer was
extracted with EtOAc (50 mL.times.2). The combined organic layers
were washed with water (30 mL), brine (30 mL), dried over
Na.sub.2SO.sub.4, filtered and evaporated. The residue was purified
by column chromatography to provide the title compound (2 g, yield:
95%) as colorless oils.
Example 42D
tert-butyl
(4-(8-carbamoyl-6-fluoro-4-((2-(trimethylsilyl)ethoxy)methyl)-4-
H-benzo[4,5]imidazo[1,2-b]pyrazol-3-yl)-3-fluorobenzyl)(methyl)carbamate
##STR00150##
A mixture of EXAMPLE 41I (100 g, 0.23 mmol), EXAMPLE 42C (85.7 g,
0.23 mmol), Na.sub.2CO.sub.3 (50 mg, 0.47 mmol) and Pd(dppf)C.sub.2
(17.1 g, 0.023 mmol) in DMF (5 mL) and H.sub.2O (1 mL) was stirred
at 80.degree. C. for 15 h under N.sub.2 atmosphere. After being
cooled to room temperature, the mixture was filtered and the
filtrate was diluted with water (20 mL). The aqueous layer was
extracted with EtOAc (50 mL.times.2). The combined organic layers
were washed with water (30 mL), brine (30 mL), dried over
Na.sub.2SO.sub.4, filtered and evaporated to give the residue which
was purified by prep-TLC to provide the title compound (110 g,
yield: 97%). LCMS (ESI) m/z: 586 (M+1).
Example 42E
6-fluoro-3-(2-fluoro-4-((methylamino)methyl)phenyl)-4H-benzo[4,5]imidazo[1-
,2-b]pyrazole-8-carboxamide
##STR00151##
A mixture of EXAMPLE 42D (110 g, 0.19 mmol) in TFA (5 mL) and DCM
(5 mL) was stirred at 10.degree. C. for 15 h. After removal of
solution in vacuum, to the residue were added MeOH (15 mL) and
K.sub.2CO.sub.3 (53 g, 0.38 mmol). The mixture was stirred at
18.degree. C. for 15 h. The mixture was filtered and the filtrate
was evaporated. The residue was partitioned between water (10 mL)
and EtOAc (10 mL). The aqueous layer was extracted with
EtOAc/THF=3/1 (20 mL.times.2). The combined organic layers were
washed with brine (20 mL), dried over Na.sub.2SO.sub.4, filtered
and evaporated to give the residue which was purified by prep-HPLC
to provide the title compound (22.45 g, yield: 34%) as a white
solid. .sup.1H NMR (400 MHz, METHANOL-d.sub.4) .cndot. ppm 2.79 (s,
3H), 4.24 (s, 2H), 4.48-5.29 (m, 27H), 7.37-7.43 (m, 2H), 7.52 (d,
J=7.78 Hz, 1H), 7.72 (d, J=9.79 Hz, 1H), 7.78 (t, J=7.78 Hz, 1H),
8.23 (s, 1H), 8.49 (br. s., 1H). LCMS (ESI) m/z: 356 (M+1).
Example 43
6-fluoro-3-(4-((methylamino)methyl)phenyl)-4H-benzo[4,5]imidazo[1,2-b]pyra-
zole-8-carboxamide
##STR00152##
This example was prepared as the method described in Example 42.
.sup.1H-NMR (400 MHz, MethanoL-d.sub.4+D.sub.2O) 2.77 (s, 3H), 4.21
(s, 2H), 7.46-7.62 (m, 3H), 7.75 (d, J=8.16 Hz, 3H), 8.26 (s, 1H),
8.53 (br. s., 1H). LCMS (ESI) m/z: 338 (M+1).
Example 44
6-fluoro-3-(2-fluoro-5-((methylamino)methyl)phenyl)-4H-benzo[4,5]imidazo[1-
,2-b]pyrazole-8-carboxamide
##STR00153##
This example was prepared as the method described in Example 42.
.sup.1H-NMR (400 MHz, DMSO-d.sub.6+D.sub.2O) 2.59 (br. s., 3H),
4.13 (br. s., 2H), 7.15-7.41 (m, 2H), 7.47-7.68 (m, 2H), 7.95-8.09
(m, 1H), 8.16-8.27 (m, 1H), 8.36 (br. s., 1H). LCMS (ESI) m/z: 356
(M+1).
Example 45
6-fluoro-3-(pyridin-4-yl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamid-
e
##STR00154##
This example was prepared as the method described in Example 42.
.sup.1H-NMR (MeOD, 400 MHz) .delta.: 7.55-7.63 (m, 2H), 7.73-7.79
(m, 1H), 8.11-8.14 (m, 1H), 8.15-8.19 (m, 1H), 8.48-8.54 (m, 2H),
8.55-8.59 (m, 1H), 10.28-10.36 (m, 1H). LCMS (ESI) m/z: 296
(M+1).
Example 46
6-fluoro-3-(4-(piperidin-3-yl)phenyl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole--
8-carboxamide
##STR00155##
Example 46A
tert-butyl
3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperi-
dine-1-carboxylate
##STR00156##
A mixture of tert-butyl 3-(4-aminophenyl)piperidine-1-carboxylate
(0.1 g, 0.362 mmol),
4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (0.101
g, 0.398 mmol), BPO (1.75 g, 0.00724 mmol) and t-BuONO (0.056 g,
0.542 mmol) in acetonitrile (3 mL) was stirred at 10.degree. C. for
16 h under N.sub.2 atmosphere. The solvent was evaporated off under
vacuum and the residue was purified by prep-TLC to provide the
title compound (0.095 g, yield: 68%).
Example 46B
6-fluoro-3-(4-(piperidin-3-yl)phenyl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole--
8-carboxamide
##STR00157##
This example was prepared as the method described in Example 42.
.sup.1H NMR (300 MHz, METHANOL-d4) .delta. ppm 1.189 (m, 2H),
2.10-2.01 (m, 2H), 3.03-3.14 (m, 3H), 3.45-3.49 (m, 2H), 7.37-7.40
(d, 2H), 7.44-7.47 (dd, 1H), 7.66-7.68 (d, 2H), 7.74-7.79 (dd, 1H),
8.22 (s, 1H), 8.53 (s, 1H). LCMS (ESI) m/z: 378 (M+1).
Example 47
6-fluoro-3-(tetrahydro-2H-pyran-4-yl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole--
8-carboxamide
##STR00158##
Example 47A
3,6-dihydro-2H-pyran-4-yl trifluoromethanesulfonate
##STR00159##
To a solution of dihydro-2H-pyran-4(3H)-one (1.8 g, 18.0 mol) in
THF (20 ml) was added LiHMDS (1 M, 21.6 ml, 21.6 mmol) at
-78.degree. C. under N.sub.2 atmosphere. After stirring for 1 h at
-78.degree. C., (CF.sub.3SO.sub.2).sub.2NPh (6.4 g, 18.0 mmol) was
added in portions. The mixture was stirred at 15.degree. C. for 16
h and quenched with aq NH.sub.4Cl solution (20 mL). The aqueous
layer was extracted with EtOAc (30 mL.times.2). The combined
organic layers were washed with water, brine, dried over
Na.sub.2SO.sub.4 and concentrated under vacuum. The residue was
purified by column chromatograph to provide the title compound as a
colorless oil (1.5 g, yield: 35.7%). LCMS (ESI) m/z: 233 (M+1).
Example 47B
2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane
##STR00160##
This example was prepared as the method described in Example
42C.
Example 47C
6-fluoro-3-(tetrahydro-2H-pyran-4-yl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole--
8-carboxamide
##STR00161##
This example was prepared as the method described in Example 46B.
.sup.1H-NMR (MeOD, 400 MHz) .delta.: 1.82-2.03 (m, 4H), 2.93-3.04
(m, 1H), 3.62 (td, J=11.70, 2.45 Hz, 2H), 4.04-4.11 (m, 2H),
7.32-7.39 (m, 1H), 7.66-7.75 (m, 2H), 8.51-8.55 (m, 1H). LCMS (ESI)
m/z: 303 (M+1).
Example 48
3-(4-(dimethylamino)cyclohexyl)-6-fluoro-4H-benzo[4,5]imidazo[1,2-b]pyrazo-
le-8-carboxamide
##STR00162##
Example 48A
4-((tert-butoxycarbonyl)amino)cyclohex-1-en-1-yl
trifluoromethanesulfonate
##STR00163##
To a solution of tert-butyl (4-oxocyclohexyl)carbamate (1 g, 4.689
mol) in THF (20 mL) was added dropwise LiHMDS (1 M, 9.4 ml, 9.378
mmol) at -78.degree. C. under N.sub.2 atmosphere. After stirring at
-78.degree. C. for 1 h, a solution of (CF.sub.3SO.sub.2).sub.2NPh
(1.84 g, 5.158 mmol) in THF (5 mL) was added. The mixture was
stirred at 15.degree. C. for 16 h, and then quenched with aq
NH.sub.4Cl solution (20 mL). The aqueous layer was extracted with
EtOAc (20 mL.times.2). The combined organic layers were washed with
water, brine, dried over Na.sub.2SO.sub.4, filtered and evaporated.
The residue was purified by column chromatograph on silica gel to
provide the title compound as a white solid (1.16 g, yield:
71.60%). LCMS (ESI) m/z: 347 (M+1).
Example 48B
tert-butyl
(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-en-1-
-yl)carbamate
##STR00164##
This example was prepared as the method described in Example
47B
Example 48C
3-(4-(dimethylamino)cyclohexyl)-6-fluoro-4H-benzo[4,5]imidazo[1,2-b]pyrazo-
le-8-carboxamide
##STR00165##
This example was prepared as the methods described in Example 47C
and Example 2. .sup.1H-NMR (MeOD, 400 MHz) .delta.: 1.63-1.87 (m,
3H), 1.91-2.10 (m, 2H), 2.20-2.46 (m, 3H), 2.81 (s, 4H), 2.90 (s,
3H), 3.19-3.30 (m, 1H), 7.34-7.44 (m, 1H), 7.64-7.75 (m, 2H),
7.78-7.85 (m, 1H), 8.38-8.73 (m, 3H).
LCMS (ESI) m/z: 344 (M+1).
Example 49
6-fluoro-3-(4-methylpiperazine-1-carbonyl)-4H-benzo[4,5]imidazo[1,2-b]pyra-
zole-8-carboxamide
##STR00166##
Example 49A
ethyl
8-bromo-6-fluoro-4-((2-(trimethylsilyl)ethoxy)methyl)-4H-benzo[4,5]i-
midazo[1,2-b]pyrazole-3-carboxylate
##STR00167##
To a solution of EXAMPLE 41B (3.2 g, 9.812 mol) in THF (50 mL) was
added NaH (785 g, 19.625 mmol) in portions at 0.degree. C. under
N.sub.2 atmosphere. After stirring at 15.degree. C. for 0.5 h and
cooling to 0.degree. C., SEMCl (3.3 g, 19.625 mmol) was added
dropwise thereto. The mixture was stirred at 15.degree. C. for
another 16 h and then quenched with aq NH.sub.4Cl saturated
solution (30 mL). The aqueous layer was extracted with EtOAc (30
mL.times.3). The combined organic layers were washed with water,
brine, dried over Na.sub.2SO.sub.4 and evaporated. The residue was
purified by column chromatograph to provide the title compound as a
yellow solid (2.16 g, yield: 48.21%). LCMS (ESI) m/z: 456, 458 (M,
M+2).
Example 49B
8-bromo-6-fluoro-4-((2-(trimethylsilyl)ethoxy)methyl)-4H-benzo[4,5]imidazo-
[1,2-b]pyrazole-3-carboxylic acid
##STR00168##
A mixture of EXAMPLE 49A (2.16 g, 4.726 mmol) and NaOH (950 g,
23.632 mmol) in a mixed solvent of MeOH/H.sub.2O (2:1) (30 mL) was
stirred at 80.degree. C. for 16 h. The resultant mixture was
adjusted to pH 3-4 with 1N HCl. The aqueous layer was extracted
with EtOAc (30 mL.times.2). The combined organic layers were washed
with water, brine, dried over Na.sub.2SO.sub.4 and evaporated to
provide the title compound (1.73 g, yield: 85.22%) which could be
used in the next step without further purification.
Example 49C
tert-butyl
4-(8-bromo-6-fluoro-4-((2-(trimethylsilyl)ethoxy)methyl)-4H-ben-
zo[4,5]imidazo[1,2-b]pyrazole-3-carbonyl)piperazine-1-carboxylate
##STR00169##
A mixture of tert-butyl piperazine-1-carboxylate (415 g, 2.241
mmol), EXAMPLE 49B (800 g, 1.868 mmol), HATU (1.42 g, 3.735 mmol)
and Et.sub.3N (567 g, 5.603 mmol) in DMF (15 mL) was stirred at
15.degree. C. for 16 h under N.sub.2 atmosphere. The mixture was
quenched with H.sub.2O (10 mL). The aqueous layer was extracted
with EtOAc (20 mL.times.2). The combined organic layers were washed
with water, brine, dried over Na.sub.2SO.sub.4 and evaporated. The
residue was purified by column chromatograph to provide the title
compound (1 g, yield: 90%). LCMS (ESI) m/z: 596, 598 (M, M+2).
Example 49D
tert-butyl
4-(8-cyano-6-fluoro-4-((2-(trimethylsilyl)ethoxy)methyl)-4H-ben-
zo[4,5]imidazo[1,2-b]pyrazole-3-carbonyl)piperazine-1-carboxylate
##STR00170##
A mixture of EXAMPLE 49C (400 g, 0.671 mmol), Zn (87 g, 1.341
mmol), Zn(CN).sub.2 (158 g, 1.341 mmol), DPPF (75 g, 0.134 mmol)
and Pd.sub.2(DBA).sub.3 (61 g, 0.0671 mmol) in DMF (10 mL) was
stirred at 120.degree. C. under N.sub.2 atmosphere for 10 hours.
After being cooled to room temperature, the resultant mixture was
diluted with water (20 mL). The aqueous layer was extracted with
EtOAc (30 mL.times.3). The combined organic layers were washed with
water, brine, dried over Na.sub.2SO.sub.4, filtered and evaporated.
The residue was purified by column chromatograph to provide the
title compound (350 g, yield: 96.15%). LCMS (ESI) m/z: 543
(M+1).
Example 49E
tert-butyl
4-(8-carbamoyl-6-fluoro-4-((2-(trimethylsilyl)ethoxy)methyl)-4H-
-benzo[4,5]imidazo[1,2-b]pyrazole-3-carbonyl)piperazine-1-carboxylate
##STR00171##
To a mixture of EXAMPLE 49D (400 g, 0.737 mmol) and K.sub.2CO.sub.3
(510 g, 3.685 mmol) in DMSO (10 mL) was added H.sub.2O.sub.2 (5 mL)
at 0-5.degree. C. After the dropwise addition was completed, the
mixture was stirred at 15.degree. C. for 1 h, and quenched with aq
Na.sub.2SO.sub.3 solution (20 mL). The aqueous layer was extracted
with EtOAc (30 mL.times.3). The combined organic layers were washed
with water, brine, dried over Na.sub.2SO.sub.4 and evaporated. The
residue was purified by column chromatograph to provide the title
compound (400 g, yield: 96.85%). LCMS (ESI) m/z: 561 (M+1).
Example 49F
6-fluoro-3-(piperazine-1-carbonyl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-c-
arboxamide
##STR00172##
A mixture of EXAMPLE 49E (100 g, 0.178 mmol) in TFA (1 mL) and DCM
(1 mL) was stirred at 15.degree. C. for 16 h. After removal of
solution in vacuum, to the residue were added K.sub.2CO.sub.3 (123
g, 0.892 mmol) and MeOH (2 mL). The mixture was stirred at
15.degree. C. for 2 h. The mixture was filtered and the filtrate
was evaporated to provide the title compound which could be used
directly in the next step without further purification.
Example 49G
6-fluoro-3-(4-methylpiperazine-1-carbonyl)-4H-benzo[4,5]imidazo[1,2-b]pyra-
zole-8-carboxamide
##STR00173##
A mixture of EXAMPLE 49F (59 g, 0.179 mmol), formaldehyde (40 g,
0.358 mmol) and Na(CN)BH.sub.3 (56 g, 0.894 mmol) in MeOH (2 mL)
was stirred at 15.degree. C. for 16 h. After evaporation off
solvent in vacuum, the residue was purified by prep-HPLC to provide
the title compound (8.14 g, yield: 13.23%) as a white solid.
.sup.1H-NMR (MeOD, 400 MHz) .delta.: 2.68 (s, 3H), 2.99 (d, J=4.64
Hz, 4H), 4.00 (br. s., 4H), 7.46-7.54 (m, 1H), 7.74-7.84 (m, 1H),
8.12-8.20 (m, 1H), 8.24-8.35 (m, 2H). LCMS (ESI) m/z: 345
(M+1).
Example 50
3-(1-(cyclopropylmethyl)piperidin-4-yl)-4,4,6-trifluoro-4H-pyrazolo[15-.al-
pha.]indole-8-carboxamide
##STR00174##
Example 50A
ethyl (E)-4-(dimethylamino)-2-oxobut-3-enoate
##STR00175##
A solution of ethyl 2-oxopropanoate (5.0 g, 43.1 mmol) in DMF-DMA
(5.0 g, 42.0 mmol) was stirred at 20.degree. C. for 16 h. The
resultant mixture was evaporated to provide the title compound (7.0
g, crude) as brown oil which could be used directly in the next
step without further purification.
Example 50B
ethyl 1-(2,6-dibromo-4-fluorophenyl)-1H-pyrazole-5-carboxylate
##STR00176##
A mixture of EXAMPLE 1D (5.0 g, 17.6 mmol), EXAMPLE 50A (6.0 g,
35.2 mmol) in EtOH (100 ml) and conc HCl (2.4 mL) was stirred at
80.degree. C. for 16 h. After removal of solution in vacuum, the
residue was purified by column chromatograph to provide the title
compound (3.6 g, yield: 46.8%) as a yellow solid.
Example 50C
1-(2,6-dibromo-4-fluorophenyl)-1H-pyrazole-5-carboxylic acid
##STR00177##
A mixture of EXAMPLE 50B (3.6 g, 9.18 mmol) and NaOH (2.2 g, 55.1
mmol) in MeOH (20 mL) and water (2 mL) was stirred at 20.degree. C.
for 1 h. After removal of solution in vacuum, the residue was
diluted with water (50 mL) and adjusted to pH 3 with 2 N HCl. The
aqueous layer was extracted with dichloromethane (50 mL.times.3).
The combined organic layers were dried over Na.sub.2SO.sub.4,
filtered and evaporated to provide the title compound (3.2 g,
97.0%) which could be used directly in the next step without
further purification.
Example 50D
1-(2,6-dibromo-4-fluorophenyl)-N-methoxy-N-methyl-1H-pyrazole-5-carboxamid-
e
##STR00178##
A mixture of EXAMPLE 50C (3.2 g, 8.82 mmol),
O,N-Dimethyl-hydroxylamine (1.7 g, 17.6 mmol), HATU (4.0 g, 10.6
mmol) and Et.sub.3N (3.6 g, 35.3 mmol) in dry DMF (2 mL) was
stirred at 20.degree. C. for 16 h under N.sub.2 atmosphere. After
removal of solution in vacuum, the residue was purified by column
chromatograph to provide the title compound (3.4 g, yield: 94.4%)
as a yellow solid.
Example 50E
8-bromo-6-fluoro-4H-pyrazolo[1,5-.alpha.]indol-4-one
##STR00179##
To a mixture of EXAMPLE 50D (3.2 g, 7.90 mmol) in dry THF (5 mL)
was added dropwise n-BuLi (2.8 mL, 7.11 mmol) at -78.degree. C.
under N.sub.2 atmosphere. After being stirred at -78.degree. C. for
0.5 h, the mixture was quenched with sat aq NH.sub.4Cl solution (30
mL). The aqueous layer was extracted with DCM (50 mL.times.2). The
combined organic layers were evaporated. The residue was washed
with MeOH (30 mL) to provide the title compound (1.5 g, yield:
71.4%) as a bright yellow solid. LCMS (ESI) m/z: 267, 269 (M,
M+2).
Example 50F
methyl
6-fluoro-4-oxo-4H-pyrazolo[1,5-.alpha.]indole-8-carboxylate
##STR00180##
A mixture of EXAMPLE 50E (1.3 g, 4.89 mmol), Pd(dppf)Cl.sub.2 (0.71
g, 0.98 mmol), Pd(OAc).sub.2 (0.22 g, 0.98 mmol), DPPP (0.81 g,
1.96 mmol), PPh.sub.3 (0.51 g, 1.96 mmol), Xantphos (1.13 g, 1.96
mmol) and Et.sub.3N (3 mL) in MeOH (20 mL) and DMF (60 mL) was
stirred at 80.degree. C. for 16 h under CO atmosphere (3 atms).
After being cooled to 20.degree. C., the mixture was filtered and
the filtrate was evaporated. The residue was purified by column
chromatograph to provide the title compound (0.9 g, yield: 75.0%)
as a yellow solid. LCMS (ESI) m/z: 247 (M+1).
Example 50G
methyl
6-fluorospiro[pyrazolo[1,5-.alpha.]indole-4,2'-[1,3]dithiolane]-8-c-
arboxylate
##STR00181##
A mixture of EXAMPLE 50F (0.9 g, 3.66 mmol), 2-ethanedithiol (0.69
g, 7.32 mmol) and BF.sub.3-Et.sub.2O (1.0 g, 7.32 mmol) in dry DCM
(30 mL) was stirred at 50.degree. C. for 24 h under N.sub.2
atmosphere. After cooled to room temperature, the mixture was
diluted with DCM (30 mL). The combined organic layers were washed
with 10% NaOH (30 mL), dried over Na.sub.2SO.sub.4, filtered and
evaporated to give the residue which was purified by column
chromatograph on silica gel (PE: EtOAc=10:1) to provide the title
compound (0.5 g, yield: 42.4%) as a yellow solid. LCMS (ESI) m/z:
323 (M+1).
Example 50H
methyl
3-bromo-6-fluorospiro[pyrazolo[1,5-.alpha.]indole-4,2'-[1,3]dithiol-
ane]-8-carboxylate
##STR00182##
A mixture of EXAMPLE 50G (500 g, 1.55 mmol) and NBS (276 g, 1.55
mmol) in THF (20 mL) was stirred at 40.degree. C. for 16 h. After
being cooled to 20.degree. C., the mixture was evaporated and the
residue was purified by column chromatograph to provide the title
compound (470 g, yield: 75.7%) as a light yellow solid. LCMS (ESI)
m/z: 401, 403 (M, M+2).
Example 50I
methyl
3-bromo-4,4,6-trifluoro-4H-pyrazolo[1,5-.alpha.]indole-8-carboxylat-
e
methyl
3-bromo-6-fluoro-4-oxo-4H-pyrazolo[1,5-.alpha.]indole-8-carboxylate
##STR00183##
To a solution of NIS (2.1 g, 9.38 mmol) in DCM (20 mL) was added
HF.Py (3.5 mL) dropwise at -78.degree. C. under N.sub.2 atmosphere.
After stirring at -78.degree. C. for 10 min, EXAMPLE 50H (470 g,
1.17 mmol) was added. The resultant mixture was stirred at
-78.degree. C. for 16 h and then quenched with sat aq NaHCO.sub.3
solution (30 mL). The aqueous layer was extracted with EtOAc (30
mL.times.2). The combined organic layers were washed with sat aq
Na.sub.2SO.sub.3 solution (30 mL) and evaporated off solvent under
vacuum. The residue was purified by column chromatograph to provide
EXAMPLE 50IA as a yellow solid (250 g, yield: 61.6%) and provide
EXAMPLE 50IB (110 g, yield: 27.2%) as a white solid.
Example 50J
3-(1-(tert-butoxycarbonyl)-1,2,3,6-tetrahydropyridin-4-yl)-4,4,6-trifluoro-
-4H-pyrazolo[1,5-.alpha.]indole-8-carboxylic acid
##STR00184##
A mixture of EXAMPLE 50IA (200 g, 0.499 mmol), tert-butyl
4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-
-carboxylate (185 g, 0.598 mmol), Pd(dppf)Cl.sub.2 (37 g, 0.050
mmol) and K.sub.2CO.sub.3 (138 g, 0.997 mmol) in DMF (9 mL) and
H.sub.2O (3 mL) was stirred at 90.degree. C. for 16 h under N.sub.2
atmosphere. After the mixture was cooled to room temperature and
concentrated in vacuum, the residue was dissolved in water (20 mL)
and adjusted to pH 3 with 1 N HCl. The aqueous layer was extracted
with DCM (50 mL.times.3).
The combined organic layers were dried over Na.sub.2SO.sub.4,
filtered and evaporated to provide the title compound (220 g,
crude) without further purification.
Example 50K
tert-butyl
4-(8-carbamoyl-4,4,6-trifluoro-4H-pyrazolo[1,5-.alpha.]indol-3--
yl)-5,6-dihydropyridine-1(2H)-carboxylate
##STR00185##
A mixture of EXAMPLE 50J (220 g, 0.51 mmol),
(NH.sub.4).sub.2CO.sub.3 (97 g, 1.01 mmol), Et.sub.3N (0.2 mL, 1.53
mmol) and HATU (252 g, 0.66 mmol) in DMF (8 mL) was stirred at
20.degree. C. for 16 h. The reaction mixture was concentrated under
vacuum and the residue was purified by column chromatograph to
provide the title compound as a yellow solid (70 g, yield: 32.0%).
LCMS (ESI) m/z: 435 (M+1).
Example 50L
tert-butyl
4-(8-carbamoyl-4,4,6-trifluoro-4H-pyrazolo[1,5-.alpha.]indol-3--
yl)piperidine-1-carboxylate
##STR00186##
A mixture of EXAMPLE 50K (35 g, 0.08 mmol) and 10% Pd/C (20 mg) in
dry DCM (20 mL) and MeOH (10 mL) was hydrogenated at 50.degree. C.
for 16 h under H.sub.2 (1 atm). The mixture was filtered and the
filtrate was evaporated to provide the title compound (30 g, yield:
85.7%) which could be used directly in the next step without
further purification. LCMS (ESI) m/z: 437 (M+1).
Example 50M
4,4,6-trifluoro-3-(piperidin-4-yl)-4H-pyrazolo[1,5-.alpha.]indole-8-carbox-
amide
##STR00187##
A mixture of EXAMPLE 50L (200 g, 0.466 mmol) in TFA (2 mL) and DCM
(6 mL) was stirred at 20.degree. C. for 2 h. The resultant mixture
was evaporated to provide the title compound which could be used
directly in the next step without further purification (30 g,
crude).
Example 50N
3-(1-(cyclopropylmethyl)piperidin-4-yl)-4,4,6-trifluoro-4H-pyrazolo[1,5-.a-
lpha.]indole-8-carboxamide
##STR00188##
A mixture of EXAMPLE 50M (30 g, 0.069 mmol),
cyclopropanecarbaldehyde (10 g, 0.138 mmol), Ti(O-ipr).sub.4 (39 g,
0.138 mmol) and Na(CN)BH.sub.3 (13 g, 0.207 mmol) in MeOH (8 mL)
was stirred at 60.degree. C. for 16 h under N.sub.2 atmosphere. The
resultant mixture was quenched with water (10 mL). The aqueous
layer was extracted with DCM (20 mL.times.3). The combined organic
layers were evaporated and the residue was purified by prep-HPLC to
provide the title compound as a white solid (5 g, yield: 18.5%).
.sup.1H-NMR (400 MHz, MethanoL-d.sub.4) .delta. ppm 0.41 (d, J=4.89
Hz, 2H), 0.72-0.81 (m, 2H), 1.13 (br. s., 1H), 1.93-2.13 (m, 2H),
2.31 (d, J=13.93 Hz, 2H), 2.87-3.12 (m, 5H), 3.66 (d, J=11.17 Hz,
2H), 7.78-7.82 (m, 1H), 7.85 (s, 1H), 7.97 (dd, J=9.91, 2.64 Hz,
1H), 8.07 (s, 1H). LCMS (ESI) m/z: 391 (M+1).
Example 51
3-(1-ethylpiperidin-4-yl)-6-fluoro-4-hydroxy-4H-pyrazolo[1,5-.alpha.]indol-
e-8-carboxamide
##STR00189##
Example 51A
tert-butyl
4-(8-carbamoyl-6-fluoro-4-oxo-4H-pyrazolo[1,5-.alpha.]indol-3-y-
l)-3,6-dihydropyridine-1(2H)-carboxylate
##STR00190##
This example was prepared as described in Example 50K. LCMS (ESI)
m/z: 413 (M+1).
Example 51B
tert-butyl
4-(8-carbamoyl-6-fluoro-4-hydroxy-4H-pyrazolo[1,5-.alpha.]indol-
-3-yl)piperidine-1-carboxylate
##STR00191##
A mixture of EXAMPLE 51A (50 g, 0.121 mmol) and 10% Pd/C (10 mg) in
dry MeOH (10 mL) was hydrogenated at 50.degree. C. for 16 h under
H.sub.2 (1 atm). The mixture was filtered and the filtrate was
evaporated to provide the title compound (40 g, yield: 80.0%) which
could be used directly in the next step without further
purification. LCMS (ESI) m/z: 417 (M+1).
Example 51C
6-fluoro-4-hydroxy-3-(piperidin-4-yl)-4H-pyrazolo[1,5-.alpha.]indole-8-car-
boxamide
##STR00192##
This example was prepared as described in Example 50M.
Example 51D
3-(1-ethylpiperidin-4-yl)-6-fluoro-4-hydroxy-4H-pyrazolo[15-.alpha.]indole-
-8-carboxamide
##STR00193##
A mixture of EXAMPLE 51C (25 g, 0.079 mmol), 40% acetaldehyde (0.1
mL) and Na(CN)BH.sub.3 (20 mg, 0.316 mmol) in MeOH (5 ml) was
stirred at 10.degree. C. for 16 h. The resultant mixture was
diluted with water (10 mL). The aqueous layer was extracted with
DCM (20 mL.times.3). The combined organic layers were evaporated to
give the residue which was purified by prep-HPLC to provide the
title compound (9.40 g, yield: 34.8%) as a white solid. .sup.1H-NMR
(400 MHz, MethanoL-d.sub.4) .delta. ppm 1.11-1.18 (m, 3H),
1.77-1.96 (m, 2H), 2.01-2.16 (m, 2H), 2.61 (br. s., 2H), 2.81 (br.
s., 3H), 3.27 (br. s., 2H), 5.72 (s, 1H), 7.59 (dd, J=7.22, 2.45
Hz, 1H), 7.70 (d, J=10.42 Hz, 1H), 7.76 (s, 1H), 7.99 (br. s., 1H),
8.32 (br. s., 1H), 10.09 (br. s., 1H). LCMS (ESI) m/z: 345
(M+1).
Example 52
3-(1-ethylpiperidin-4-yl)-6-fluoro-4-methyl-4H-benzo[4,5]imidazo[1,2-b]pyr-
azole-8-carboxamide
##STR00194##
Example 52A
tert-butyl
4-(8-carbamoyl-6-fluoro-4-methyl-4H-benzo[4,5]imidazo[1,2-b]pyr-
azol-3-yl)piperidine-1-carboxylate
##STR00195##
A mixture of EXAMPLE 1I (30 g, 0.075 mmol), K.sub.2CO.sub.3 (31 g,
0.224 mmol) and CH.sub.3I (32 g, 0.224 mmol) in DMF (3 mL) was
stirred at 10.degree. C. for 1 h. The reaction was quenched with
water (10 mL). The aqueous layer was extracted with EtOAc (10
mL.times.3). The combined organic layers were dried over
Na.sub.2SO.sub.4, filtered and evaporated to provide the title
compound which could be used directly in the next step without
further purification.
Example 52B
6-fluoro-4-methyl-3-(piperidin-4-yl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-
-carboxamide
##STR00196##
A mixture of EXAMPLE 52A (31 g, 0.074 mmol) in DCM (1 mL) and TFA
(0.2 mL) was stirred at 10.degree. C. for 2 h. The mixture was
evaporated to provide the title compound which could be used
directly in the next step without further purification.
Example 52C
3-(1-ethylpiperidin-4-yl)-6-fluoro-4-methyl-4H-benzo[4,5]imidazo[1,2-b]pyr-
azole-8-carboxamide
##STR00197##
This example was prepared as the method described in Example 51D.
.sup.1H-NMR (400 MHz, METHANOL-d4) .delta. ppm 1.23-1.26 (t, 3H),
1.91-1.97 (m, 2H), 2.11-2.14 (d, 2H), 2.55 (t, 2H), 2.78-2.80 (m,
2H), 3.04-3.07 (m, 2H), 3.32 (2H), 3.87 (s, 2H), 7.48-8.50 (m, 1H),
7.64-7.67 (m, 1H), 7.73 (s, 1H), 8.54 (s, 1H). LCMS (ESI) m/z: 344
(M+1).
##STR00198##
Example 53
6-fluoro-3-(4-methylpiperidin-4-yl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8--
carboxamide
##STR00199##
Example 53A
1-(tert-butyl) 4-methyl 4-methylpiperidine-1,4-dicarboxylate
##STR00200##
To a solution of 1-tert-butyl 4-methyl piperidine-1,4-dicarboxylate
(36.5 g, 0.15 mol) in anhydrous THF (400 mL) was added dropwise
LiHMDS (1 M, 300 mL) at -78.degree. C. under N.sub.2 atmosphere.
After stirring at -78.degree. C. for 30 min, a solution of MeI
(42.6 g, 0.3 mol) in THF (100 mL) was added dropwise thereto. The
reaction mixture was stirred at -78.degree. C. for 2 hours and
warmed to 15.degree. C. and stirred for further 20 hours. After
completion of the reaction, the mixture was quenched with sat aq
NH.sub.4Cl solution (500 mL). The aqueous layer was extracted with
EtOAc (500 mL.times.3). The combined organic layers were dried over
Na.sub.2SO.sub.4, filtered and evaporated. The residue was purified
by column chromatograph to provide the title compound (30 g, yield:
78%). LCMS (ESI) m/z: 258 (M+1).
Example 53B
tert-butyl 4-(hydroxymethyl)-4-methylpiperidine-1-carboxylate
##STR00201##
To a solution of LiAlH.sub.4 (3.7 g, 97.5 mmol) in anhydrous THF
(40 mL) was added dropwise a solution of EXAMPLE 53A (10 g, 39
mmol) in anhydrous THF (80 mL) at 0.degree. C. under N.sub.2
atmosphere. After the dropwise addition was completed, the reaction
mixture was stirred at 0.degree. C. for 2.5 hours, and then
quenched with water (4 mL), 15% aq NaOH solution (4 mL) and water
(12 mL). The resultant mixture was stirred at 0.degree. C. for
further 20 minutes. The mixture was filtered and the solid was
washed with EtOAc (50 mL.times.4). The combined organic layers were
dried over Na.sub.2SO.sub.4, filtered and evaporated to provide the
title compound (9 g, crude) which could be used directly in the
next step without further purification.
Example 53C
tert-butyl 4-(cyanomethyl)-4-methylpiperidine-1-carboxylate
##STR00202##
This example was prepared as the method described in Examples
1A-1B.
Example 53D
6-fluoro-3-(4-methylpiperidin-4-yl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8--
carboxamide
##STR00203##
This example was prepared as described in Examples 1E-1J. .sup.1H
NMR (400 MHz, MeOD) .delta.: 8.51 (s, 1H), 7.81 (s, 1H), 7.69 (dd,
J=2.4 Hz/J=10.2 Hz, 1H), 7.45 (dd, J=2.4 Hz/J=8.0 Hz, 1H),
3.33-3.39 (m, 2H), 3.12-3.32 (m, 2H), 2.42-2.46 (m, 2H), 2.03-2.08
(m, 2H), 1.46 (s, 3H). LCMS (ESI) m/z: 316 (M+1).
Example 54
3-(1-ethyl-4-methylpiperidin-4-yl)-6-fluoro-4H-benzo[4,5]imidazo[1,2-b]pyr-
azole-8-carboxamide
##STR00204##
This example was prepared as described in Example 52C (10 g, yield:
38%). .sup.1H NMR (400 MHz, DMSO) .delta.: 10.58 (s, 1H), 8.28 (s,
1H), 8.13 (s, 1H), 7.80 (s, 1H), 7.61 (dd, J=2.8 Hz/J=7.2 Hz, 1H),
7.49 (t, J=2.4 Hz, 1H), 2.75-2.78 (m, 2H), 2.50-2.54 (m, 4H),
2.18-2.20 (m, 2H), 1.73-1.78 (m, 2H), 1.30 (s, 3H), 1.05 (t, J=7.2
Hz, 3H). LCMS (ESI) m/z: 344 (M+1).
Example 55
3-(1-cyclopropyl-4-methylpiperidin-4-yl)-6-fluoro-4H-benzo[4,5]imidazo[1,2-
-b]pyrazole-8-carboxamide
##STR00205##
This example was prepared as described in Example 4. .sup.1H-NMR
(400 MHz, MethanoL-d.sub.4) 0.77 (d, J=5.40 Hz, 4H), 1.41-1.45 (m,
3H), 1.90-2.01 (m, 2H), 2.28-2.44 (m, 3H), 3.03 (br. s., 2H), 3.27
(br. s., 2H), 7.39 (dd, J=8.16, 2.51 Hz, 1H), 7.73 (dd, J=10.92,
2.38 Hz, 1H), 7.79 (s, 1H), 8.41 (br. s., 1H). LCMS (ESI) m/z: 356
(M+1).
Example 56
6-fluoro-3-(1-(2-hydroxy-2-methylpropyl)-4-methylpiperidin-4-yl)-4H-benzo[-
4,5]imidazo[1,2-b]pyrazole-8-carboxamide
##STR00206##
This example was prepared as the method described in Example 6.
.sup.1H-NMR (400 MHz, DMSO-d.sub.4) .delta. ppm 1.13 (s, 6H), 1.28
(s, 3H), 1.86 (t, J=10.23 Hz, 2H), 2.20 (d, J=15.43 Hz, 2H), 2.62
(s, 2H), 2.76 (br. s., 2H), 3.04 (d, J=4.02 Hz, 2H), 7.48 (dd,
J=8.34, 2.57 Hz, 1H), 7.56 (dd, J=10.92, 2.64 Hz, 1H), 7.79 (s,
1H), 8.31 (s, 1H). LCMS (ESI) m/z: 388 (M+1).
Example 57
3-(1-(cyclopropylmethyl)-4-methylpiperidin-4-yl)-6-fluoro-4H-benzo[4,5]imi-
dazo[1,2-b]pyrazole-8-carboxamide
##STR00207##
This example was prepared as the method described in Example 5.
.sup.1H-NMR (400 MHz, MethanoL-d.sub.4) .delta. ppm 0.37 (d, J=3.89
Hz, 2H), 0.73 (d, J=7.53 Hz, 2H), 1.02-1.14 (m, 1H), 1.44 (br. s.,
3H), 2.08 (d, J=11.29 Hz, 2H), 2.37-2.66 (m, 2H), 2.94 (br. s.,
3H), 3.34-3.63 (m, 3H), 7.38 (dd, J=8.09, 2.57 Hz, 1H), 7.71 (dd,
J=10.92, 2.51 Hz, 1H), 7.79 (s, 1H), 7.77-7.81 (m, 1H), 8.51 (s,
1H). LCMS (ESI) m/z: 370 (M+1).
Example 58
3-(1-(4,4-difluorocyclohexyl)-4-methylpiperidin-4-yl)-6-fluoro-4H-benzo[4,-
5]imidazo[1,2-b]pyrazole-8-carboxamide
##STR00208##
This example was prepared as the method described in Example 5.
.sup.1H-NMR (400 MHz, DMSO-d.sub.4) .delta. ppm 1.22 (s, 3H),
1.33-1.49 (m, 1H), 1.70 (br. s., 6H), 1.92-2.12 (m, 1H), 2.31-2.38
(m, 1H), 2.59-2.64 (m, 1H), 7.40-7.62 (m, 2H), 7.74 (s, 1H). LCMS
(ESI) m/z: 434 (M+1).
Example 59
6-fluoro-3-(4-methyl-1-(tetrahydro-2H-pyran-4-yl)piperidin-4-yl)-4H-benzo[-
4,5]imidazo[1,2-b]pyrazole-8-carboxamide
##STR00209##
This example was prepared as the method described in Example 5.
.sup.1H NMR (400 MHz, METHANOL-d.sub.4) 1.05 (t, J=7.22 Hz, 1H),
1.36 (s, 3H), 1.50-1.60 (m, 1H), 1.82 (d, J=11.92 Hz, 3H),
2.21-2.27 (m, 1H), 2.44-2.56 (m, 1H), 2.79 (br. s., 2H), 3.35-3.42
(m, 1H), 3.90-4.05 (m, 1H), 7.32-7.38 (m, 1H), 7.71 (s, 1H). LCMS
(ESI) m/z: 400 (M+1).
Example 60
6-fluoro-3-(1-(2-fluoroethyl)-4-methylpiperidin-4-yl)-4H-benzo[4,5]imidazo-
[1,2-b]pyrazole-8-carboxamide
##STR00210##
This example was prepared as the method described in Example 3.
.sup.1H NMR (400 MHz, METHANOL-d.sub.4) ppm 1.45 (s, 3H), 2.01-2.05
(m, 2H), 2.24-2.47 (m, 2H), 3.05 (m, 2H), 3.24-3.25 (m, 1H),
3.26-3.27 (m, 1H), 3.33-3.34 (m, 1H), 4.70-4.72 (m, 1H), 4.82-4.93
(m, 1H), 7.37-7.39 (m, 1H), 7.68-7.79 (d, 1H), 7.81 (s, 1H), 8.45
(br. s., 1H). LCMS (ESI) m/z: 362 (M+1).
Example 61
6-fluoro-3-(4-methyl-1-(2,2,2-trifluoroethyl)piperidin-4-yl)-4H-benzo[4,5]-
imidazo[1,2-b]pyrazole-8-carboxamide
##STR00211##
This example was prepared as the method described in Example 3.
.sup.1H NMR (400 MHz, METHANOL-d.sub.4) ppm 1.37 (s, 3H), 1.79-1.91
(m, 2H), 2.16-2.27 (m, 2H), 2.58-2.69 (m, 2H), 2.79-2.89 (m, 2H),
2.98-3.10 (m, 2H), 7.33-7.39 (m, 1H), 7.66-7.75 (m, 2H). LCMS (ESI)
m/z: 398 (M+1).
Example 62
6-fluoro-3-(4-methyl-1-(3,3,3-trifluoropropyl)piperidin-4-yl)-4H-benzo[4,5-
]imidazo[1,2-b]pyrazole-8-carboxamide
##STR00212##
This example was prepared as the method described in Example 3.
.sup.1H NMR (400 MHz, METHANOL-d.sub.4) 1.42 (s, 3H), 1.92-2.05 (m,
2H), 2.38 (d, J=14.93 Hz, 2H), 2.54-2.71 (m, 2H), 2.86 (d, J=9.79
Hz, 2H), 2.93-3.07 (m, 2H), 3.14 (d, J=11.17 Hz, 2H), 7.37 (dd,
J=8.16, 2.51 Hz, 1H), 7.70 (dd, J=10.92, 2.51 Hz, 1H), 7.76 (s,
1H), 8.37 (br. s., 1H). LCMS (ESI) m/z: 412 (M+1).
Example 63
3-(1-((1-cyanocyclopropyl)methyl)-4-methylpiperidin-4-yl)-6-fluoro-4H-benz-
o[4,5]imidazo[1,2-b]pyrazole-8-carboxamide
##STR00213##
This example was prepared as the method described in Example 3.
.sup.1H NMR (400 MHz, METHANOL-d.sub.4) .delta. ppm 1.05 (d, J=2.26
Hz, 2H), 1.32-1.38 (m, 2H), 1.40 (s, 3H), 1.89-2.05 (m, 2H), 2.33
(d, J=15.69 Hz, 2H), 2.69 (s, 4H), 3.02 (br. s., 2H), 7.38 (dd,
J=8.09, 2.57 Hz, 1H), 7.68-7.83 (m, 2H), 8.28 (br. s., 1H). LCMS
(ESI) m/z: 395 (M+1).
Example 64
3-(1-((1-cyanocyclobutyl)methyl)-4-methylpiperidin-4-yl)-6-fluoro-4H-benzo-
[4,5]imidazo[1,2-b]pyrazole-8-carboxamide
##STR00214##
This example was prepared as the method described in Example 3.
.sup.1H NMR (400 MHz, METHANOL-d.sub.4) 1.38 (s, 3H), 1.85-1.94 (m,
2H), 2.00-2.09 (m, 1H), 2.18-2.31 (m, 5H), 2.42-2.52 (m, 2H), 2.63
(t, J=9.22 Hz, 2H), 2.81 (s, 2H), 2.88 (d, J=5.65 Hz, 2H), 7.36
(dd, J=8.03, 2.26 Hz, 1H), 7.69 (d, J=2.26 Hz, 1H), 7.73 (s, 1H),
8.30 (br. s., 1H). LCMS (ESI) m/z: 409 (M+1).
Example 65
6-fluoro-3-(4-methyl-1-(2-(methylsulfonyl)ethyl)piperidin-4-yl)-4H-benzo[4-
,5]imidazo[1,2-b]pyrazole-8-carboxamide
##STR00215##
This example was prepared as the method described in Example 3.
.sup.1H NMR (400 MHz, METHANOL-d.sub.4) ppm 1.40 (s, 3H), 1.87-1.98
(m, 2H), 2.28-2.38 (m, 2H), 2.63-2.80 (m, 2H), 2.95-3.05 (m, 2H),
3.07 (s, 3H), 3.07-3.14 (m, 2H), 3.38-3.47 (m, 2H), 7.33-7.40 (m,
1H), 7.66-7.73 (m, 1H), 7.73-7.77 (m, 1H), 8.20-8.37 (m, 1H). LCMS
(ESI) m/z: 422 (M+1).
Example 66
6-fluoro-3-(4-methyl-1-((tetrahydro-2H-pyran-4-yl)methyl)piperidin-4-yl)-4-
H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide
##STR00216##
This example was prepared as the method described in Example 3.
.sup.1H NMR (400 MHz, METHANOL-d.sub.4) 1.25-1.33 (m, 2H), 1.37 (s,
3H), 1.70 (d, J=13.30 Hz, 2H), 1.80-1.89 (m, 3H), 2.22 (br. s.,
2H), 2.23 (br. s., 2H), 2.38 (br. s., 2H), 2.67 (br. s., 2H),
3.40-3.47 (m, 2H), 3.94 (dd, J=11.67, 2.89 Hz, 2H), 7.36 (dd,
J=8.16, 2.51 Hz, 1H), 7.69 (d, J=2.51 Hz, 1H), 7.72 (br. s., 1H).
LCMS (ESI) m/z: 414 (M+1).
Example 67
3-(1-((1-aminocyclopropyl)methyl)-4-methylpiperidin-4-yl)-6-fluoro-4H-benz-
o[4,5]imidazo[1,2-b]pyrazole-8-carboxamide
##STR00217##
This example was prepared as the method described in Example 3.
.sup.1H NMR (400 MHz, METHANOL-d.sub.4) ppm 0.72-0.82 (m, 2H),
0.93-1.00 (m, 2H), 1.40 (s, 3H), 1.91-2.03 (m, 2H), 2.26-2.37 (m,
2H), 2.66 (s, 4H), 2.94-3.06 (m, 2H), 7.33-7.41 (m, 1H), 7.67-7.73
(m, 1H), 7.73-7.77 (m, 1H), 8.22-8.48 (m, 2H). LCMS (ESI) m/z: 385
(M+1).
Example 68
6-fluoro-3-(4-methyl-1-(oxetan-3-ylmethyl)piperidin-4-yl)-4H-benzo[4,5]imi-
dazo[1,2-b]pyrazole-8-carboxamide
##STR00218##
This example was prepared as the method described in Example 3.
.sup.1H NMR (400 MHz, CHLOROFORM-d) ppm 1.36 (s, 3H), 1.78-1.88 (m,
2H), 2.17-2.25 (m, 2H), 2.36 (br. s., 2H), 2.57-2.68 (m, 2H), 2.72
(d, J=7.03 Hz, 2H), 4.38-4.47 (m, 2H), 4.60-4.63 (m, 1H), 4.80-4.82
(m, 2H), 7.33-7.39 (m, 1H), 7.68-7.76 (m, 2H). LCMS (ESI) m/z: 386
(M+1).
Example 69
6-fluoro-3-(1-(2-methoxyethyl)-4-methylpiperidin-4-yl)-4H-benzo[4,5]imidaz-
o[1,2-b]pyrazole-8-carboxamide
##STR00219##
This example was prepared as the method described in Example 3.
.sup.1H NMR (400 MHz, METHANOL-d.sub.4) 1.45 (s, 3H), 2.07 (ddd,
J=14.68, 10.85, 3.58 Hz, 2H), 2.46 (d, J=14.81 Hz, 2H), 3.12 (br.
s., 2H), 3.23 (t, J=4.83 Hz, 2H), 3.41 (s, 5H), 3.66-3.73 (m, 2H),
7.39 (dd, J=8.16, 2.51 Hz, 1H), 7.71 (dd, J=10.92, 2.51 Hz, 1H),
7.80 (s, 1H), 8.52 (s, 1H). LCMS (ESI) m/z: 374 (M+1).
Example 70
6-fluoro-3-(1-((1-hydroxycyclopropyl)methyl)-4-methylpiperidin-4-yl)-4H-be-
nzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide
##STR00220##
This example was prepared as the method described in Example 3.
.sup.1H NMR (400 MHz, METHANOL-d.sub.4) .delta. ppm 0.64-0.74 (m,
2H), 0.84-0.93 (m, 2H), 1.46 (s, 3H), 2.04-2.18 (m, 2H), 2.50 (d,
J=15.18 Hz, 2H), 3.16 (br. s., 4H), 3.47-3.68 (m, 2H), 7.36-7.43
(m, 1H), 7.68-7.75 (m, 1H), 7.79-7.84 (m, 1H), 8.48-8.65 (m, 1H).
LCMS (ESI) m/z: 386 (M+1).
Example 71
6-fluoro-3-(4-methyl-methyl-((3-methyloxetan-3-yl)methyl)piperidin-4-yl)-4-
H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide
##STR00221##
This example was prepared as the method described in Example 3.
.sup.1H NMR (400 MHz, METHANOL-d.sub.4) ppm 1.38 (s, 3H), 1.46 (s,
3H), 1.81-1.93 (m, 2H), 2.18-2.29 (m, 2H), 2.33-2.54 (m, 2H),
2.54-2.84 (m, 4H), 4.31-4.35 (m, 2H), 4.49-4.54 (m, 2H), 7.34-7.39
(m, 1H), 7.68-7.75 (m, 2H). LCMS (ESI) m/z: 400 (M+1).
Example 72
6-fluoro-3-(1-(3-methoxypropyl)-4-methylpiperidin-4-yl)-4H-benzo[4,5]imida-
zo[1,2-b]pyrazole-8-carboxamide
##STR00222##
This example was prepared as the method described in Example 3.
.sup.1H NMR (400 MHz, METHANOL-d.sub.4) 1.45 (s, 3H), 1.94-2.01 (m,
2H), 2.02-2.12 (m, 2H), 2.47 (d, J=13.05 Hz, 2H), 2.89-3.20 (m,
4H), 3.34 (s, 3H), 3.39 (br. s., 2H), 3.45-3.52 (m, 2H), 7.38 (dd,
J=8.09, 2.57 Hz, 1H), 7.71 (dd, J=10.92, 2.51 Hz, 1H), 7.79 (s,
1H), 8.55 (s, 1H). LCMS (ESI) m/z: 434 (M+1).
Example 73
6-fluoro-3-(4-methyl-1-((1-(methylsulfonyl)cyclopropyl)methyl)piperidin-4--
yl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide
##STR00223##
This example was prepared as the method described in Example 3.
.sup.1H NMR (400 MHz, METHANOL-d.sub.4) 0.95-1.01 (m, 2H), 1.38 (s,
3H), 1.41-1.49 (m, 2H), 1.83-1.96 (m, 2H), 2.27 (d, J=13.30 Hz,
2H), 2.55 (br. s., 2H), 2.86 (s, 2H), 2.92 (br. s., 2H), 3.24 (s,
3H), 7.36 (dd, J=8.16, 2.51 Hz, 1H), 7.67-7.78 (m, 2H). LCMS (ESI)
m/z: 448 (M+1).
Example 74
6-fluoro-3-(4-methyl-1-(thiazol-2-ylmethyl)piperidin-4-yl)-4H-benzo[4,5]im-
idazo[1,2-b]pyrazole-8-carboxamide
##STR00224##
This example was prepared as the method described in Example 3.
.sup.1H NMR (400 MHz, METHANOL-d.sub.4) ppm 1.36-1.42 (m, 3H),
1.86-1.97 (m, 2H), 2.23-2.33 (m, 2H), 2.63-2.73 (m, 2H), 2.89-2.98
(m, 2H), 4.02-4.07 (m, 2H), 7.32-7.40 (m, 1H), 7.58-7.63 (m, 1H),
7.68-7.73 (m, 1H), 7.74 (s, 1H), 7.75-7.79 (m, 1H), 8.25-8.35 (m,
1H). LCMS (ESI) m/z: 413 (M+1).
Example 75
6-fluoro-3-(4-methyl-1-(methylsulfonyl)piperidin-4-yl)-4H-benzo[4,5]imidaz-
o[1,2-b]pyrazole-8-carboxamide
##STR00225##
This example was prepared as the method described in Example 3.
.sup.1H-NMR (MeOD, 400 MHz) .delta.: 1.38-1.46 (m, 3H), 1.88 (ddd,
J=13.68, 9.66, 3.76 Hz, 2H), 2.32 (d, J=15.06 Hz, 2H), 2.78 (s,
3H), 3.00-3.17 (m, 2H), 3.46-3.53 (m, 2H), 7.35-7.41 (m, 1H),
7.69-7.75 (m, 1H), 7.77-7.79 (m, 1H), 8.46-8.53 (m, 1H). LCMS (ESI)
m/z: 394 (M+1).
Example 76
6-fluoro-3-(1-(3-fluorocyclobutyl)-4-methylpiperidin-4-yl)-4H-benzo[4,5]im-
idazo[1,2-b]pyrazole-8-carboxamide
##STR00226##
This example was prepared as the method described in Example 2.
.sup.1H-NMR (400 MHz, MethanoL-d.sub.4) .delta. ppm 1.45 (s, 3H),
1.96-2.18 (m, 2H), 2.38-2.74 (m, 6H), 2.94 (br. s., 4H), 3.74-3.93
(m, 1H), 5.12-5.32 (m, 1H), 7.41 (dd, J=8.16, 2.38 Hz, 1H), 7.67
(dd, J=10.79, 2.26 Hz, 1H), 7.79 (s, 1H), 8.52 (br. s., 1H). LCMS
(ESI) m/z: 388 (M+1).
Example 77
6-fluoro-3-(4-methyl-1-(thiophen-2-ylmethyl)piperidin-4-yl)-4H-benzo[4,5]i-
midazo[1,2-b]pyrazole-8-carboxamide
##STR00227##
This example was prepared as the method described in Example 2.
.sup.1H NMR (400 MHz, METHANOL-d.sub.4) 1.34 (s, 3H), 1.82 (ddd,
J=13.36, 9.41, 3.45 Hz, 2H), 2.13-2.27 (m, 1H), 2.32-2.53 (m, 1H),
2.69 (br. s., 2H), 3.72 (s, 2H), 6.87-7.01 (m, 2H), 7.25-7.39 (m,
2H), 7.62-7.75 (m, 2H). LCMS (ESI) m/z: 412 (M+1).
Example 78
3-(1-((1-ethylpiperidin-4-yl)methyl)-4-methylpiperidin-4-yl)-6-fluoro-4H-b-
enzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide
##STR00228##
This example was prepared as the method described in Example 2.
.sup.1H-NMR (400 MHz, METHANOL-d4) .delta. ppm 1.32-1.35 (t, 3H),
1.42 (s, 3H), 1.47-1.51 (d, 2H), 1.99-2.08 (m, 5H), 2.35-2.38 (d,
2H), 2.64-2.65 (d, 2H), 2.89 (m, 2H), 3.06 (t, 2H), 3.11-3.15 (m,
4H), 3.51-3.54 (d, 2H), 7.37-7.39 (m, 1H), 7.70-7.74 (m, 1H), 7.77
(s, 1H), 8.446 (s, 2H). LCMS (ESI) m/z: 441 (M+1).
Example 79
6-fluoro-3-(4-methyl-1-((1-methylazetidin-3-yl)methyl)piperidin-4-yl)-4H-b-
enzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide
##STR00229##
This example was prepared as the method described in Example 2.
.sup.1H-NMR (400 MHz, METHANOL-d4) .delta. ppm 1.32 (s, 3H),
1.89-1.95 (m, 2H), 2.29-2.33 (d, 2H), 2.60 (d, 2H), 2.86-2.91,
2.64-2.65 (m, 7H), 3.18 (m, 1H), 3.84-3.88 (t, 2H), 4.15-4.20 (t,
2H), 7.36-7.39 (m, 1H), 7.70-7.73 (m, 1H), 7.77 (s, 1H), 8.41 (s,
2H). LCMS (ESI) m/z: 399 (M+1).
Example 80
ethyl
2-((4-(8-carbamoyl-6-fluoro-4H-benzo[4,5]imidazo[1,2-b]pyrazol-3-yl)-
-4-methylpiperidin-1-yl)methyl)cyclopropanecarboxylate
##STR00230##
This example was prepared as the method described in Example 2.
.sup.1H NMR (400 MHz, METHANOL-d.sub.4) 0.86-1.34 (m, 6H),
1.35-1.49 (m, 2H), 1.57-2.01 (m, 4H), 2.09-2.28 (m, 2H), 2.44-2.70
(m, 2H), 2.99-3.27 (m, 2H), 3.36-3.47 (m, 2H), 3.53-3.75 (m, 2H),
4.06-4.26 (m, 3H), 7.50-7.65 (m, 1H), 7.74-7.85 (m, 1H), 8.05 (br.
s., 1H). LCMS (ESI) m/z: 442 (M+1).
Example 81
ethyl
3-(1-((2-(dimethylcarbamoyl)cyclopropyl)methyl)-4-methylpiperidin-4--
yl)-6-fluoro-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide
##STR00231##
This example was prepared as the method described in Example 2.
.sup.1H NMR (400 MHz, METHANOL-d.sub.4) 0.97-1.29 (m, 2H), 1.47 (s,
2H), 1.65 (s, 1H), 2.08-2.30 (m, 3H), 2.63 (d, J=15.3 Hz, 1H), 2.85
(s, 1H), 2.92-3.01 (m, 3H), 3.01-3.12 (m, 2H), 3.12-3.27 (m, 2H),
3.29 (s, 2H), 3.34-3.47 (m, 2H), 3.55-3.77 (m, 2H), 7.56-7.70 (m,
1H), 7.78-7.85 (m, 1H), 8.12 (d, J=6.5 Hz, 1H). LCMS (ESI) m/z: 441
(M+1).
Example 82
6-fluoro-3-(1-isobutyl-4-methylpiperidin-4-yl)-4H-benzo[4,5]imidazo[1,2-b]-
pyrazole-8-carboxamide
##STR00232##
This example was prepared as the method described in Example 2.
.sup.1H-NMR (MeOD, 400 MHz) .delta.: 1.00-1.02 (d, 6H), 1.43 (s,
3H), 2.03-2.07 (m, 3H), 2.10-2.11 (d, 2H), 2.81-2.83 (d, 2H), 3.03
(bs, 2H), 3.31 (bs, 2H), 7.35-7.38 (dd, 1H), 7.67-7.71 (s, 1H),
7.77 (s, 1H), 8.53 (bs, 1H). LCMS (ESI) m/z: 372 (M+1).
Example 83
6-fluoro-3-(4-methyl-1-((4-methylthiazol-5-yl)methyl)piperidin-4-yl)-4H-be-
nzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide
##STR00233##
This example was prepared as the method described in Example 2.
.sup.1H NMR (400 MHz, METHANOL-d4) .delta. ppm 1.41 (s, 3H),
1.89-2.01 (m, 2H), 2.30-2.39 (m, 2H), 2.43 (s, 3H), 2.73-2.86 (m,
2H), 2.97-3.15 (m, 2H), 4.01-4.20 (m, 2H), 7.30-7.47 (m, 1H),
7.65-7.86 (m, 2H), 8.90-9.04 (m, 1H). LCMS (ESI) m/z: 427
(M+1).
Example 84
6-fluoro-3-(4-methyl-1-((1-methyl-1H-imidazol-2-yl)methyl)piperidin-4-yl)--
4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide
##STR00234##
This example was prepared as the method described in Example 2.
.sup.1H NMR (400 MHz, METHANOL-d.sub.4) .delta. ppm 1.32-1.44 (m,
3H), 1.78-1.96 (m, 2H), 2.18-2.33 (m, 2H), 2.46-2.62 (m, 2H),
2.71-2.88 (m, 2H), 3.73-3.77 (m, 2H), 3.81 (s, 3H), 7.01-7.11 (m,
1H), 7.18-7.23 (m, 1H), 7.33-7.40 (m, 1H), 7.73 (s, 2H), 8.28-8.44
(m, 1H). LCMS (ESI) m/z: 410 (M+1).
Example 85
3-(1-((1,2-dimethyl-1H-imidazol-5-yl)methyl)-4-methylpiperidin-4-yl)-6-flu-
oro-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide
##STR00235##
This example was prepared as the method described in Example 2.
.sup.1H NMR (400 MHz, METHANOL-d.sub.4) .delta. ppm 1.38 (s, 3H),
1.83-1.92 (m, 2H), 2.27 (d, J=13.80 Hz, 2H), 2.54 (s, 5H), 2.86 (d,
J=10.92 Hz, 2H), 3.70 (s, 2H), 3.75 (s, 3H), 7.17 (s, 1H), 7.36
(dd, J=8.16, 2.51 Hz, 1H), 7.66-7.80 (m, 2H), 8.38 (br. s., 1H).
LCMS (ESI) m/z: 424 (M+1).
Example 86
3-(1'-ethyl-4-methyl-[1,4'-bipiperidin]-4-yl)-6-fluoro-4H-benzo[4,5]imidaz-
o[1,2-b]pyrazole-8-carboxamide
##STR00236##
This example was prepared as the method described in Example 2.
.sup.1H-NMR (400 MHz, MethanoL-d.sub.4) 1.09 (t, J=7.09 Hz, 3H),
1.27 (s, 3H), 1.50-1.70 (m, 2H), 1.72-1.85 (m, 2H), 1.92 (d,
J=11.54 Hz, 2H), 2.34 (br. s., 2H), 2.75 (d, J=7.40 Hz, 7H), 2.86
(br. s., 2H), 3.23 (d, J=10.42 Hz, 2H), 7.49 (d, J=8.41 Hz, 1H),
7.58 (dd, J=10.85, 2.20 Hz, 1H), 7.79 (s, 1H), 8.28 (s, 2H). LCMS
(ESI) m/z: 427 (M+1).
Example 87
6-fluoro-3-(4-methyl-1-((6-oxo-1,6-dihydropyridazin-3-yl)methyl)piperidin--
4-yl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide
##STR00237##
This example was prepared as the method described in Example 2.
.sup.1H NMR (400 MHz, MeOD) .delta.: 8.35 (s, 1H), 7.70-7.74 (m,
2H), 7.57-7.60 (d, 1H), 7.36-7.38 (t, 1H), 6.98-7.00 (d, 1H), 3.63
(s, 2H), 2.86 (m, 2H), 2.61-2.63 (m, 2H), 2.26-2.30 (d, 2H),
1.87-1.94 (m, 2H), 1.39 (s, 3H). LCMS (ESI) m/z: 424 (M+1).
Example 88
3-(1-(2-cyanoethyl)-4-methylpiperidin-4-yl)-6-fluoro-4H-benzo[4,5]imidazo[-
1,2-b]pyrazole-8-carboxamide
##STR00238##
A mixture of EXAMPLE 53D (52 g, 0.125 mmol), acrylonitrile (66 g,
1.25 mmol) and potassium carbonate (172 g, 1.25 mmol) in DMF (18
mL) was stirred at 28.degree. C. for 1 hour. After completion, the
reaction was quenched with water (10 mL). The aqueous layer was
extracted with EtOAc (20 mL.times.3). The combined organic layers
were dried over Na.sub.2SO.sub.4, filtered and evaporated. The
residue was purified by prep-HPLC to provide the title compound (31
g, yield 66.0%). .sup.1H NMR (400 MHz, METHANOL-d.sub.4) ppm 1.39
(s, 3H), 1.86-1.97 (m, 2H), 2.25-2.36 (m, 2H), 2.60-2.70 (m, 2H),
2.74 (s, 2H), 2.84-2.98 (m, 4H), 7.33-7.41 (m, 1H), 7.68-7.73 (m,
1H), 7.74 (s, 1H), 8.21-8.32 (m, 1H). LCMS (ESI) m/z: 369
(M+1).
Example 89
6-chloro-3-(1-ethyl-4-methylpiperidin-4-yl)-4H-benzo[4,5]imidazo[1,2-b]pyr-
azole-8-carboxamide
##STR00239##
This example was prepared as described in Example 53, substituting
(2,6-dibromo-4-chlorophenyl)hydrazine for
(2,6-dibromo-4-fluorophenyl)hydrazine. .sup.1H-NMR (MeOD, 400 MHz)
.delta.: 1.32-1.39 (t, 3H), 1.46 (m, 1H), 2.52-2.55 (s, 3H),
2.06-2.08 (m, 2H), 2.47-2.48 (m, 2H), 3.09-3.11 (m, 3H), 3.34-3.41
(m, 3H), 7.63 (s, 1H), 7.83 (s, 1H), 7.97-7.97 (d, 1H), 8.54 (bs,
1H). LCMS (ESI) m/z: 360 (M+1).
Example 90
3-(1-ethyl-3-methylpyrrolidin-3-yl)-6-fluoro-4H-benzo[4,5]imidazo[1,2-b]py-
razole-8-carboxamide
##STR00240##
This example was prepared as described in Example 53, substituting
tert-butyl 3-(hydroxymethyl)-3-methylpyrrolidine-1-carboxylate for
tert-butyl 4-(hydroxymethyl)-4-methylpiperidine-1-carboxylate.
.sup.1H NMR (400 MHz, METHANOL-d.sub.4) ppm 1.38 (s, 3H), 1.64 (s,
3H), 2.25-2.42 (m, 1H), 2.59-2.76 (m, 1H), 3.27-3.32 (m, 2H),
3.39-3.53 (m, 1H), 3.54-3.71 (m, 2H), 3.71-3.88 (m, 1H), 7.33-7.39
(m, 1H), 7.57-7.70 (m, 1H), 7.76-7.90 (m, 1H), 8.28-8.80 (m, 1H).
LCMS (ESI) m/z: 330 (M+1).
Example 91
3-(1,3-dimethylpyrrolidin-3-yl)-6-fluoro-4H-benzo[4,5]imidazo[1,2-b]pyrazo-
le-8-carboxamide
##STR00241##
This example was prepared as the method described in Example 90.
.sup.1H-NMR (400 MHz, MethanoL-d.sub.4) .delta. ppm 8.52 (br. s.,
1H), 7.84 (s, 1H), 7.67 (dd, J=2.5, 10.9 Hz, 1H), 7.38 (dd, J=2.5,
8.0 Hz, 1H), 3.74 (d, J=11.3 Hz, 1H), 3.67-3.49 (m, 2H), 3.40 (d,
J=11.3 Hz, 1H), 2.96 (s, 3H), 2.73-2.60 (m, 1H), 2.34 (td, J=7.8,
13.4 Hz, 1H), 1.64 (s, 3H). LCMS (ESI) m/z: 316 (M+1).
Example 92
6-fluoro-3-(1-isopropyl-3-methylpyrrolidin-3-yl)-4H-benzo[4,5]imidazo[1,2--
b]pyrazole-8-carboxamide
##STR00242##
This example was prepared as the method described in Example 90.
.sup.1H NMR (400 MHz, METHANOL-d.sub.4) ppm 1.38-1.52 (m, 6H), 1.71
(d, J=2.26 Hz, 3H), 2.32-2.46 (m, 1H), 2.63-2.82 (m, 1H), 3.38-3.70
(m, 3H), 3.76-4.11 (m, 2H), 7.58-7.70 (m, 1H), 7.76-7.86 (m, 1H),
8.15-8.29 (m, 1H). LCMS (ESI) m/z: 344 (M+1).
Example 93
3-(1-(cyclopropylmethyl)-3-methylpyrrolidin-3-yl)-6-fluoro-4H-benzo[4,5]im-
idazo[1,2-b]pyrazole-8-carboxamide
##STR00243##
This example was prepared as the method described in Example 5.
.sup.1H NMR (400 MHz, METHANOL-d.sub.4) ppm 0.41-0.52 (m, 2H),
0.70-0.82 (m, 2H), 1.10-1.26 (m, 1H), 1.66 (s, 3H), 2.27-2.39 (m,
1H), 2.63-2.75 (m, 1H), 3.17 (d, J=7.15 Hz, 2H), 3.44-3.58 (m, 1H),
3.59-3.78 (m, 2H), 3.79-3.94 (m, 1H), 7.27-7.40 (m, 1H), 7.55-7.67
(m, 1H), 7.77-7.89 (m, 1H), 8.43-8.69 (m, 1H). LCMS (ESI) m/z: 356
(M+1).
Example 94
6-fluoro-3-(3-methyl-1-(oxetan-3-yl)pyrrolidin-3-yl)-4H-benzo[4,5]imidazo[-
1,2-b]pyrazole-8-carboxamide
##STR00244##
This example was prepared as the method described in Example 5.
.sup.1H NMR (400 MHz, METHANOL-d.sub.4) .delta. ppm 1.58 (s, 3H),
2.01-2.10 (m, 1H), 2.26-2.35 (m, 1H), 2.68-2.74 (m, 1H), 2.79-2.87
(m, 1H), 2.87-2.96 (m, 1H), 2.96-3.03 (m, 1H), 3.78-3.85 (m, 1H),
4.62-4.72 (m, 1H), 4.74-4.81 (m, 1H), 7.31-7.40 (m, 1H), 7.64-7.71
(m, 1H), 7.72-7.77 (m, 1H). LCMS (ESI) m/z: 358 (M+1).
Example 95
6-fluoro-3-(1-(2-fluoroethyl)-3-methylpyrrolidin-3-yl)-4H-benzo[4,5]imidaz-
o[1,2-b]pyrazole-8-carboxamide
##STR00245##
This example was prepared as the method described in Example 3.
.sup.1H-NMR (MeOD, 400 MHz) .delta.: 1.635 (s, 1H), 2.243-2.263 (m,
1H), 2.522-2.554 (m, 1H), 3.288-3.321 (d, 1H), 3.325 (s, 2H),
3.329-3.337 (m, 1H), 3.391-3.414 (m, 1H), 3.632-3.659 (d, 1H),
4.730-4.860 (dt, 2H), 7.291-7.317 (dd, 1H), 7.586-7.619 (dd, 1H),
7.788 (s, 1H), 8.445 (bs, 1H), LCMS (ESI) m/z: 348 (M+1).
Example 96
3-(1-((2,2-difluorocyclopropyl)methyl)-3-methylpyrrolidin-3-yl)-6-fluoro-4-
H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide
##STR00246##
This example was prepared as the method described in Example 3.
.sup.1H NMR (400 MHz, METHANOL-d.sub.4) ppm 1.34-1.46 (m, 1H) 1.64
(s, 3H) 1.67-1.79 (m, 1H) 2.03-2.11 (m, 1H) 2.20-2.31 (m, 1H)
2.52-2.63 (m, 1H) 3.13-3.24 (m, 1H) 3.24-3.31 (m, 2H) 3.37-3.48 (m,
1H) 3.48-3.58 (m, 1H) 3.59-3.67 (m, 1H) 7.29-7.39 (m, 1H) 7.57-7.67
(m, 1H) 7.76-7.84 (m, 1H) 8.35-8.54 (m, 1H) LCMS (ESI) m/z: 392
(M+1).
Example 97
6-fluoro-3-(3-methyl-1-(2,2,2-trifluoroethyl)pyrrolidin-3-yl)-4H-benzo[4,5-
]imidazo[1,2-b]pyrazole-8-carboxamide
##STR00247##
This example was prepared as the method described in Example 3.
.sup.1H NMR (400 MHz, METHANOL-d.sub.4) ppm 1.74 (s, 3H), 2.39-2.54
(m, 1H), 2.74-2.88 (m, 1H), 3.69-3.82 (m, 1H), 3.82-3.95 (m, 2H),
3.97-4.14 (m, 1H), 4.36-4.50 (m, 2H), 7.55-7.64 (m, 1H), 7.73-7.83
(m, 1H), 8.12-8.20 (m, 1H). LCMS (ESI) m/z: 384 (M+1).
Example 98
6-fluoro-3-(3-methyl-1-(2-(methylsulfonyl)ethyl)pyrrolidin-3-yl)-4H-benzo[-
4,5]imidazo[1,2-b]pyrazole-8-carboxamide
##STR00248##
This example was prepared as the method described in Example 3.
.sup.1H NMR (400 MHz, METHANOL-d.sub.4) ppm 1.60 (s, 3H), 2.05-2.15
(m, 1H), 2.18-2.28 (m, 1H), 2.63-2.69 (m, 1H), 2.69-2.78 (m, 1H),
3.01-3.10 (m, 1H), 3.11 (s, 3H), 3.26-3.31 (m, 1H), 3.34-3.41 (m,
2H), 3.41-3.50 (m, 1H), 3.50-3.60 (m, 1H), 7.35-7.45 (m, 1H),
7.63-7.70 (m, 1H), 7.72 (s, 1H), 8.22 (s, 1H). LCMS (ESI) m/z: 408
(M+1).
Example 99
6-fluoro-3-(3-methyl-1-(3,3,3-trifluoropropyl)pyrrolidin-3-yl)-4H-benzo[4,-
5]imidazo[1,2-b]pyrazole-8-carboxamide
##STR00249##
This example was prepared as the method described in Example 3.
.sup.1H NMR (400 MHz, METHANOL-d.sub.4) ppm 1.62 (s, 3H), 2.16-2.25
(m, 1H), 2.43-2.53 (m, 1H), 2.58-2.72 (m, 1H), 3.08-3.14 (m, 1H),
3.16-3.29 (m, 1H), 3.34-3.39 (m, 1H), 3.41-3.47 (m, 1H), 7.32-7.41
(m, 1H), 7.63-7.71 (m, 1H), 7.74-7.83 (m, 1H), 8.24-8.34 (m, 1H).
LCMS (ESI) m/z: 398 (M+1).
Example 100
3-(1-((1-aminocyclopropyl)methyl)-3-methylpyrrolidin-3-yl)-6-fluoro-4H-ben-
zo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide
##STR00250##
This example was prepared as the method described in Example 3.
.sup.1H NMR (400 MHz, METHANOL-d.sub.4) ppm 0.85 (s, 1H), 1.00 (s,
1H), 1.62 (s, 3H), 2.07-2.17 (m, 1H), 2.34-2.44 (m, 1H), 2.85 (s,
1H), 2.94-3.01 (m, 1H), 3.04-3.12 (m, 1H), 3.20 (d, J=9.41 Hz, 1H),
7.33-7.39 (m, 1H), 7.64-7.70 (m, 1H), 7.75-7.80 (m, 1H), 7.83-7.85
(m, 1H), 8.02-8.05 (m, 1H), 8.34-8.47 (m, 1H). LCMS (ESI) m/z: 371
(M+1).
Example 101
3-(1-((1-cyanocyclobutyl)methyl)-3-methylpyrrolidin-3-yl)-6-fluoro-4H-benz-
o[4,5]imidazo[1,2-b]pyrazole-8-carboxamide
##STR00251##
This example was prepared as the method described in Example 3.
.sup.1H NMR (400 MHz, METHANOL-d.sub.4) 1.60 (s, 3H), 2.00-2.11 (m,
2H), 2.13-2.23 (m, 1H), 2.25-2.40 (m, 3H), 2.45-2.58 (m, 2H),
2.65-2.70 (m, 1H), 2.72-2.80 (m, 1H), 2.93 (s, 1H), 2.99-3.06 (m,
1H), 3.14-3.23 (m, 2H), 7.38-7.44 (m, 1H), 7.69 (dd, J=10.85, 2.57
Hz, 1H), 7.74 (s, 1H), 8.33 (br. s., 1H).
LCMS (ESI) m/z: 395 (M+1).
Example 102
3-(1-((1-cyanocyclopropyl)methyl)-3-methylpyrrolidin-3-yl)-6-fluoro-4H-ben-
zo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide
##STR00252##
This example was prepared as the method described in Example 3.
.sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 0.92 (d, J=2.26 Hz, 2H),
1.16-1.24 (m, 2H), 1.48 (s, 3H), 1.87-1.97 (m, 1H), 2.05 (s, 1H),
2.55 (d, J=7.53 Hz, 4H), 2.91 (s, 2H), 7.43-7.50 (m, 1H), 7.51-7.61
(m, 1H), 7.79 (s, 1H). LCMS (ESI) m/z: 381 (M+1).
Example 103
3-(1-(2-cyanoethyl)-3-methylpyrrolidin-3-yl)-6-fluoro-4H-benzo[4,5]imidazo-
[1,2-b]pyrazole-8-carboxamide
##STR00253##
This example was prepared as the method described in Example 88.
.sup.1H NMR (400 MHz, METHANOL-d.sub.4) ppm 1.61 (s, 3H), 2.06-2.16
(m, 1H), 2.23-2.33 (m, 1H), 2.80 (d, J=6.40 Hz, 1H), 2.83-2.91 (m,
1H), 2.93-3.02 (m, 1H), 3.03-3.12 (m, 1H), 3.27 (d, J=9.29 Hz, 2H),
7.37-7.44 (m, 1H), 7.64-7.72 (m, 1H), 7.76 (s, 1H), 8.14-8.26 (m,
1H). LCMS (ESI) m/z: 355 (M+1).
Example 104
3-(1-(cyclopropylmethyl)-3-methylazetidin-3-yl)-6-fluoro-4H-benzo[4,5]imid-
azo[1,2-b]pyrazole-8-carboxamide
##STR00254##
This example was prepared as the method described in Example 93.
.sup.1H NMR (400 MHz, MeOD) .delta.: 8.51 (s, 1H), 7.96 (s, 1H),
7.70-7.73 (dd, 1H), 7.39-7.41 (dd, 1H), 4.39-4.32 (d, 2H),
4.23-4.26 (d, 2H), 3.15-3.17 (d, 2H), 1.87 (s, 3H), 1.06-1.08 (m,
1H), 0.69-0.74 (m, 2H), 0.42-0.46 (m, 2H). LCMS (ESI) m/z: 342
(M+1).
##STR00255##
Example 105
6-fluoro-3-(1-isopropyl-4-methylpiperidin-4-yl)-4H-benzo[4,5]imidazo[1,2-b-
]pyrazole-8-carboxamide
##STR00256##
Example 105A
tert-butyl
4-(1-cyano-2-ethoxy-2-oxoethylidene)-4-piperidine-1-carboxylate
##STR00257##
A mixture of tert-butyl 4-oxopiperidine-1-carboxylate (100 g, 0.5
mol), ethyl 2-cyanoacetate (56.5 g, 0.5 mol), NH.sub.4OAc (19.2 g,
0.25 mol) and HOAc (15 g, 0.25 mol) in toluene (1 L) was stirred at
120.degree. C. for 5-6 h to remove water by a Dean-Stark trap.
After removal of solvent in vacuum, the residue was partitioned
between EtOAc (500 mL) and water (500 mL), the aqueous layer was
extracted with EtOAc (500 mL.times.3). The combined organic layers
were washed with brine (500 mL), dried over Na.sub.2SO.sub.4,
filtered and evaporated. The residue was purified by pulping with
PE/EtOAc=10/1 (300 mL). The white solid was collected by filtration
to provide the title compound (90 g, 61% yield). .sup.1H NMR (400
MHz, CHLOROFORM-d) .delta. ppm 1.38 (t, J=7.15 Hz, 3H), 1.50 (s,
9H), 2.79 (t, J=5.90 Hz, 2H), 3.15 (t, J=5.83 Hz, 2H), 3.56 (t,
J=5.71 Hz, 2H), 3.63 (t, J=5.83 Hz, 2H), 4.31 (q, J=7.15 Hz, 2H).
LCMS (ESI) m/z: 295 (M+1).
Example 105B
tert-butyl
4-(1-cyano-2-ethoxy-2-oxoethyl)-4-methylpiperidine-1-carboxylat-
e
##STR00258##
To a mixture of CuI (86.3 g, 0.454 mol) in dry THF (1.7 L) was
added dropwise 3M methylmagnesium bromide (378 mL, 1.13 mol) at
-60-70.degree. C. under N.sub.2 atmosphere. After stirring at
-10.degree. C.-0.degree. C. for 1 h and cooling to -60-70.degree.
C., a solution of EXAMPLE 105A (133.5 g, 0.454 mol) in THF (300 mL)
was added. The mixture was stirred at 20.degree. C. for 15 h and
then cooled to 0.degree. C. and quenched with sat aq NH.sub.4Cl
solution (1.2 L). After filtration through a pad of Celite, the
aqueous layer was extracted with EtOAc (600 mL.times.3). The
combined organic layers were washed with brine (500 mL), dried over
Na.sub.2SO.sub.4, filtered and evaporated to provide the crude
title compound (142 g) as a yellow oil which was used directly in
the next step without further purification.
Example 105C
2-(1-(tert-butoxycarbonyl)-4-methylpiperidin-4-yl)-2-cyanoacetic
acid
##STR00259##
To a solution of EXAMPLE 105B (142 g, crude, 0.458 mol) in a
mixture of THF/MeOH=10:1 (1.2 L) was added dropwise a solution of
NaOH (73.3 g, 1.82 mol) in water (320 mL) at 0.degree. C. After the
dropwise addition was completed, the mixture was stirred at
20.degree. C. for 2 h, and then diluted by adding water (320 mL).
The aqueous layer was extracted with EtOAc (500 mL.times.3). The
combined organic layers were washed with water (200 mL.times.2).
The combined aqueous layer was adjusted to pH 3-4 by 1N HCl and
extracted with DCM/MeOH=10:1 (300 mL.times.6). The combined
DCM/MeOH organic layer was washed with brine (800 mL) and then
dried over Na.sub.2SO.sub.4, filtered and evaporated to provide the
crude title compound (111.5 g) as a yellow solid which was used
directly in the next step without further purification.
Example 105D
tert-butyl 4-(cyanomethyl)-4-methylpiperidine-1-carboxylate
##STR00260##
A mixture of EXAMPLE 105C (111.5 g, crude, 0.395 mol) and Cu.sub.2O
(11.4 g, 79.08 mmol) in acetonitrile (900 mL) was stirred at
80.degree. C. for 2 h. After being cooled to room temperature, the
mixture was evaporated and the residue was dissolved in EtOAc (1 L)
and filtered through a pad of Celite to remove insolubles. The
filter residue was washed with EtOAc (250 mL.times.2). To the
filtrate was added THF (150 mL) to dissolve the precipitates. The
organic layer was washed with water, water/brine=1:1 (300 mL),
dried over Na.sub.2SO.sub.4, filtered and evaporated. The residue
was purified by pulping with PE/EtOAc=10/1 (300 mL). The white
solid was collected by filtration to provide the title compound (98
g). LCMS (ESI) m/z: 239 (M+1).
Example 105E
tert-butyl
4-(1-cyano-2-oxoethyl)-4-methylpiperidine-1-carboxylate
##STR00261##
To a mixture of EXAMPLE 105D (50 g, 0.21 mol) in THF (400 mL) was
added dropwise 2M LDA (160 mL, 0.32 mol) at -60-70.degree. C. under
N.sub.2 atmosphere. After stirring at -60-70.degree. C. for 1 h,
ethyl formate (32 g, 0.43 mol) was added dropwise till completion,
followed by slowly warming up to 15.degree. C. and stirring for
another 4 h. After completion, the reaction was quenched with aq
NH.sub.4Cl solution (500 mL). The aqueous layer was extracted with
EtOAc (200 mL.times.3). The combined organic layers were washed
with water (200 mL), 1N HCl (300 mL.times.3), brine (200 mL),
thereafter dried over Na.sub.2SO.sub.4, filtered and evaporated to
give the residue which was purified by pulping with PE/EtOAc=10/1
(200 mL). The white solid was collected by filtration to provide
the title compound (45 g, 80% yield). LCMS (ESI) m/z: 267
(M+1).
Example 105F
(2,6-dibromo-4-fluorophenyl)hydrazine hydrochloride
##STR00262##
To a mixture of 2,6-dibromo-4-fluoroaniline (50 g, 0.186 mol) in
conc HCl (190 mL) was added dropwise a solution of NaNO.sub.2 (14.1
g, 0.205 mol) in water (70 mL) at -5-0.degree. C. After being
stirred at -5-0.degree. C. for 40 min, the above reaction mixture
was added dropwise in into a solution of SnCl.sub.2-2H.sub.2O
(62.95 g, 0.279 mol) in conc HCl (240 mL) at -5-0.degree. C. The
resultant mixture was slowly warmed up to 20.degree. C. and stirred
for 12 h. The solid was collected by filtration, washed with i-PrOH
(200 mL) and thereafter dried in vacuum to provide the title
compound (47 g, 78% yield) which could be used directly in the next
step without further purification. .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. ppm 2.37-2.68 (m, 1H), 6.94-7.28 (m, 1H),
7.80 (d, J=8.03 Hz, 2H), 10.13 (br. s., 3H).
Example 105G
tert-butyl
4-(5-amino-1-(2,6-dibromo-4-fluorophenyl)-1H-pyrazol-4-yl)-4-me-
thylpiperidine-1-carboxylate
##STR00263##
A mixture of EXAMPLE 105E (50 g, 187.73 mmol), KOAc (27.64 g,
281.73 mmol) and EXAMPLE 105F (72.17 g, 225.28 mmol) in ethanol
(500 ml) was stirred at 60.degree. C. for 5 h. After the reaction
was completed, to the mixture was added NaHCO.sub.3 (31.57 g,
375.78 mmol) while stirring at 80.degree. C. for another 15 h.
After being cooled to room temperature, the resultant mixture was
evaporated and the residue was dissolved with EtOAc (200 mL) and
water (200 mL). The aqueous layer was extracted with EtOAc (200
mL.times.3). The combined organic layers were washed with brine
(200 mL), dried over Na.sub.2SO.sub.4, filtered and evaporated. The
residue was purified by pulping with PE/EtOAc=10/1 (200 mL). The
white solid was collected by filtration to provide the title
compound (75 g, 75% yield) which could be used directly in the next
step without further purification.
Example 105H
tert-butyl
4-(8-bromo-6-fluoro-4H-benzo[4,5]imidazo[1,2-b]pyrazol-3-yl)-4--
methylpiperidine-1-carboxylate
##STR00264##
A mixture of EXAMPLE 105G (35 g, 65.78 mmol), Pd.sub.2(dba).sub.3
(6.02 g, 6.57 mmol), Xantphos (7.61 g, 13.16 mmol) and
Cs.sub.2CO.sub.3 (42.77 g, 131.58 mmol) in DMF (300 mL) was stirred
at 130.degree. C. for 9 h under N.sub.2 atmosphere. After being
cooled to room temperature, the resultant mixture was filtered and
the filtrate was evaporated. The residue was dissolved in EtOAc
(500 mL). The organic layer was washed with water (200 mL.times.2),
brine (200 mL.times.2), dried over Na.sub.2SO.sub.4, filtered and
evaporated to provide the crude title compound as brown oil which
could be used in the next step without further purification. LCMS
(ESI) m/z: 451, 453 (M, M+2).
Example 105I
tert-butyl
4-(8-cyano-6-fluoro-4H-benzo[4,5]imidazo[1,2-b]pyrazol-3-yl)-4--
methylpiperidine-1-carboxylate
##STR00265##
A mixture of EXAMPLE 105H (29.7 g, crude, 65.8 mmol), Zn(CN).sub.2
(15.4 g, 131.71 mmol), Pd.sub.2(dba).sub.3 (6.02 g, 6.58 mmol),
DPPF (7.30 g, 13.17 mmol) and Zn (8.65 g, 131.71 mmol) in DMF (300
mL) was stirred at 120.degree. C. for 5 h under N.sub.2 atmosphere.
After being cooled to room temperature, the mixture was filtered
and the filtrate was evaporated to give the residue which was
purified by column chromatography to provide the crude title
compound (35 g, crude) as yellow foam. LCMS (ESI) m/z: 398
(M+1).
Example 105J
tert-butyl
4-(8-carbamoyl-6-fluoro-4H-benzo[4,5]imidazo[1,2-b]pyrazol-3-yl-
)-4-methylpiperidine-1-carboxylate
##STR00266##
To a solution of EXAMPLE 105I (35 g, crude, 88.17 mmol) and 1N NaOH
(140 mL, 140 mmol) in DMSO (100 mL) was added dropwise 30%
H.sub.2O.sub.2 (40 mL) at 0.degree. C. After the dropwise addition
was completed, the reaction solution was warmed to 40-50.degree. C.
and stirred for 2 hours, and thereafter diluted with water (200 mL)
and extracted with EtOAc/THF=3/1 (200 mL.times.2). The combined
organic layers were washed with water (150 mL.times.2), brine (150
mL.times.2), dried over Na.sub.2SO.sub.4, filtered and evaporated.
The residue was purified by column chromatography to provide the
title compound (12.2 g, yield: 45%) as yellow solids. LCMS (ESI)
m/z: 416 (M+1).
Example 105K
6-fluoro-3-(4-methylpiperidin-4-yl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8--
carboxamide
##STR00267##
A solution of EXAMPLE 105J (5 g, 12 mmol) in a mixture of DCM/TFA
(50 mL/10 mL) was stirred at 20.degree. C. for 2 h. The resultant
mixture was evaporated to provide the title compound as yellow oil
which could be used in the next step without further
purification.
Example 105L
6-fluoro-3-(1-isopropyl-4-methylpiperidin-4-yl)-4H-benzo[4,5]imidazo[1,2-b-
]pyrazole-8-carboxamide
##STR00268##
A solution of EXAMPLE 105K (3.8 g, crude, 12 mmol), Na(CN)BH.sub.3
(2.8, 60 mmol) in a mixture of acetone (2.0 g, 34 mmol) and
methanol (50 mL) was stirred at 25.degree. C. for 3 h. After
removal of solution in vacuum, the residue was dissolved in
EtOAc/THF=5/1 (200 mL). The organic layers were washed with water
(50 mL.times.2), brine (50 mL), then dried over Na.sub.2SO.sub.4,
filtered and evaporated. The residue was purified by column
chromatograph to provide the title compound (4 g, yield: 90%).
.sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 1.11-1.61 (m, 9H),
1.89-2.29 (m, 2H), 2.47 (br. s., 1H), 2.55 (br. s., 1H), 2.77 (d,
J=12.05 Hz, 1H), 3.09-3.66 (m, 4H), 7.53 (dd, J=8.28, 2.51 Hz, 1H),
7.63 (dt, J=10.92, 2.26 Hz, 1H), 7.79-7.99 (m, 1H), 8.17 (br. s.,
1H), 10.23-10.75 (m, 2H), 12.49-12.93 (m, 1H). LCMS (ESI) m/z: 358
(M+1).
Example 106
6-fluoro-3-(4-methyl-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-4H-benzo[4,5-
]imidazo[1,2-b]pyrazole-8-carboxamide
##STR00269##
Example 106A
8-bromo-6-fluoro-3-(4-methyltetrahydro-2H-thiopyran-4-yl)-4H-benzo[4,5]imi-
dazo[1,2-b]pyrazole
##STR00270##
This example was prepared as described in Examples 105A-105H,
substituting dihydro-2H-thiopyran-4(3H)-one for tert-butyl
4-oxopiperidine-1-carboxylate. LCMS (ESI) m/z: 368, 370 (M,
M+2).
Example 106B
4-(8-bromo-6-fluoro-4H-benzo[4,5]imidazo[1,2-b]pyrazol-3-yl)-4-methyltetra-
hydro-2H-thiopyran 1,1-dioxide
##STR00271##
A mixture of EXAMPLE 106A (0.1 g, 0.271 mmol) and mCPBA (0.94 g,
0.542 mmol) in DCM (15 mL) and THF (3 mL) was stirred at 25.degree.
C. for 3 h. The mixture was quenched with sat aq Na.sub.2SO.sub.3
solution (20 mL). The aqueous layer was extracted with DCM (15
mL.times.3). The combined organic layers were washed with sat aq
NaHCO.sub.3 solution (20 mL), brine (15 mL), dried over
Na.sub.2SO.sub.4, filtered and evaporated to provide the title
compound which could be used directly in the next step without
further purification.
Example 106C
6-fluoro-3-(4-methyl-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-4H-benzo[4,5-
]imidazo[1,2-b]pyrazole-8-carboxamide
##STR00272##
This example was prepared as described in Examples 105I and 105J.
.sup.1H NMR (400 MHz, MeOD) .delta.: 7.8798 (s, 1H), 7.56-7.59 (d,
1H), 7.46-7.48 (d, 1H), 3.11 (m, 2H), 2.95-3.01 (m, 2H), 2.52 (m,
2H), 2.13-2.19 (m, 2H), 1.35 (s, 3H). LCMS (ESI) m/z: 365
(M+1).
Example 107
3-(1,4-diethylpiperidin-4-yl)-6-fluoro-4H-benzo[4,5]imidazo[1,2-b]pyrazole-
-8-carboxamide
##STR00273##
Example 107A
tert-butyl
4-(1-cyano-2-ethoxy-2-oxoethyl)-4-ethylpiperidine-1-carboxylate
##STR00274##
1,4-ethylpiperidin-4-yl
To a mixture of EXAMPLE 105A (1.0 g, 3.4 mmol) in THF (20 mL) was
added dropwise ethylmagnesium bromide (2.83 mL, 8.49 mmol) at
-78.degree. C. under N.sub.2 atmosphere. After being stirred at
-78.degree. C. for 1 h, the mixture was warmed to 32.degree. C. and
stirred for 15 h and then quenched with sat NH.sub.4Cl aq solution
(100 mL). The aqueous layer was extracted with EtOAc (100
mL.times.2). The combined organic layers were washed with brine
(200 mL), dried over Na.sub.2SO.sub.4, filtered and evaporated. The
residue was purified by column chromatograph to provide the title
compound (0.8 g, yield: 73%) as a colorless oil. LCMS (ESI) m/z:
325 (M+1).
Example 107B
3-(1,4-diethylpiperidin-4-yl)-6-fluoro-4H-benzo[4,5]imidazo[1,2-b]pyrazole-
-8-carboxamide
##STR00275##
This example was prepared as described in Example 105. .sup.1H-NMR
(400 MHz, MethanoL-d.sub.4) .delta. ppm 0.80 (t, J=7.47 Hz, 3H),
1.28 (t, J=7.34 Hz, 3H), 1.72 (d, J=7.40 Hz, 1H), 1.89-2.14 (m,
1H), 2.41-2.61 (m, 1H), 3.06 (d, J=7.28 Hz, 3H), 3.37-3.58 (m, 1H),
7.35 (dd, J=8.16, 2.51 Hz, 1H), 7.69 (dd, J=10.92, 2.64 Hz, 1H),
7.76 (s, 1H), 8.52 (s, 1H). LCMS (ESI) m/z: 358 (M+1).
Example 108
3-(4-cyano-1-(cyclopropylmethyl)piperidin-4-yl)-6-fluoro-4H-benzo[4,5]imid-
azo[1,2-b]pyrazole-8-carboxamide
##STR00276##
Example 108A
tert-butyl 4-cyano-4-(cyanomethyl)piperidine-1-carboxylate
##STR00277##
A solution of EXAMPLE 105A (2.0 g, 6.8 mmol) and KCN (1.71 g, 26.3
mmol) in a mixture of ethanol (20 mL)/Water (4 mL) was stirred at
70-80.degree. C. for 15 h. After removal of solution in vacuum, the
residue was dissolved by adding water (100 mL). The aqueous phase
was extracted with EtOAc (100 mL.times.2). The combined organic
layers were washed with brine (200 mL), dried over
Na.sub.2SO.sub.4, filtered and evaporated. The residue was purified
by column chromatograph to provide the title compound (1.3 g,
yield: 79%) as a white solid. LCMS (ESI) m/z: 250 (M+1).
Example 108B
tert-butyl
4-(5-amino-1-(2,6-dibromo-4-fluorophenyl)-1H-pyrazol-4-yl)-4-cy-
anopiperidine-1-carboxylate
##STR00278##
This example was prepared as described in Examples 105E-105G.
Example 108C
tert-butyl
4-(8-bromo-6-fluoro-4H-benzo[4,5]imidazo[1,2-b]pyrazol-3-yl)-4--
cyanopiperidine-1-carboxylate
##STR00279##
A mixture of EXAMPLE 108B (660 g, 1.22 mmol), CuI (70 g, 0.37
mmol), N.sup.1,N.sup.2-dimethylethane-1,2-diamine (65 g, 0.74 mmol)
and K.sub.3PO.sub.4 (780 g, 3.68 mmol) in DMF (15 mL) was stirred
at 70.degree. C. for 10 hours under N.sub.2 atmosphere. After being
cooled to room temperature, the resultant mixture was filtered
through a pad of Celite. The filtrate was evaporated and the
residue was purified by column chromatography to provide the title
compound (470 g, yield: 78%) as white solids. LCMS (ESI) m/z: 462,
464 (M, M+2).
Example 108D
3-(4-cyanopiperidine-4-yl)-6-fluoro-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8--
carboxamide
##STR00280##
This example was prepared as described in Examples 1G-1J. LCMS
(ESI) m/z: 327 (M+1).
Example 108E
3-(4-cyano-1-(cyclopropylmethyl)piperidin-4-yl)-6-fluoro-4H-benzo[4,5]imid-
azo[1,2-b]pyrazole-8-carboxamide
##STR00281##
This example was prepared as the method described in Example 5.
.sup.1H-NMR (400 MHz, MethanoL-d.sub.4) .delta. ppm 0.34 (d, J=5.90
Hz, 2H), 0.67-0.75 (m, 2H), 0.99-1.13 (m, 1H), 2.37 (br. s., 2H),
2.58 (br. s., 2H), 2.75 (d, J=6.90 Hz, 2H), 2.89-3.07 (m, 2H),
3.39-3.61 (m, 2H), 7.44 (dd, J=8.09, 2.57 Hz, 1H), 7.75 (dd,
J=10.85, 2.57 Hz, 1H), 7.90 (s, 1H), 8.34-8.47 (m, 1H). LCMS (ESI)
m/z: 381 (M+1).
Example 109
3-(1-(cyclopropylmethyl)-4-(hydroxymethyl)piperidin-4-yl)-6-fluoro-4H-benz-
o[4,5]imidazo[1,2-b]pyrazole-8-carboxamide
##STR00282##
Example 109A
4-(8-bromo-6-fluoro-4H-benzo[4,5]imidazo[1,2-b]pyrazol-3-yl)-1-(tert-butox-
ycarbonyl)piperidine-4-carboxylic acid
##STR00283##
A mixture of EXAMPLE 108C (800 g, 1.73 mmol) and 40% NaOH aq
solution (5 mL) in ethanol (25 mL) was stirred at 80-90.degree. C.
for 15 h. After being cooled to room temperature, the mixture was
acidified to pH 3-4 by 1N HCl and extracted with EtOAc (100
mL.times.2). The combined organic layers were washed with water (50
mL.times.2), brine (50 mL.times.2), dried over Na.sub.2SO.sub.4,
filtered and evaporated to provide the title compound (850 g,
purity: 79% yield: 98%) as a yellow solid which was used directly
in the next step without further purification. LCMS (ESI) m/z: 481,
483 (M, M+2).
Example 109B
tert-butyl
4-(8-bromo-6-fluoro-4H-benzo[4,5]imidazo[1,2-b]pyrazol-3-yl)-4--
(hydroxymethyl)piperidine-1-carboxylate
##STR00284##
To a mixture of EXAMPLE 109A (800 g, 1.56 mmol) in THF (15 mL) was
added 10 M BH.sub.3-DMS (1 mL, 10 mmol) at 0.degree. C. under
N.sub.2 atmosphere. After the dropwise addition was completed, the
mixture was stirred at 0.degree. C. for 2 hours, and then quenched
with MeOH (20 mL) and evaporated off solvent in vacuum. The residue
was purified by column chromatography to provide the title compound
as white solids. (508 g, yield: 70%). LCMS (ESI) m/z: 467, 469 (M,
M+2).
Example 109C
tert-butyl
4-(8-cyano-6-fluoro-4H-benzo[4,5]imidazo[1,2-b]pyrazol-3-yl)-4--
(hydroxymethyl)piperidine-1-carboxylate
##STR00285##
A mixture of EXAMPLE 109B (450 g, 0.96 mmol), Zn(CN).sub.2 (225 g,
1.92 mmol), Pd.sub.2(dba).sub.3 (176 mg, 0.19 mmol), DPPF (215 g,
0.38 mmol) and Zn (125 g, 1.92 mmol) in DMF (5 mL) was stirred at
120.degree. C. for 15 h under N.sub.2 atmosphere. After being
cooled to room temperature, the resultant mixture was filtered and
the filtrate was concentrated in vacuum. The residue was purified
by column chromatography to provide the title compound as brown
solids (387 g, yield: 87%). LCMS (ESI) m/z: 414 (M+1).
Example 109D
tert-butyl
4-(8-carbamoyl-6-fluoro-4H-benzo[4,5]imidazo[1,2-b]pyrazol-3-yl-
)-4-(hydroxymethyl)piperidine-1-carboxylate
##STR00286##
To a mixture of EXAMPLE 109C (350 g, 0.85 mmol) and K.sub.2CO.sub.3
(600 g, 4.34 mmol) in DMSO (10 mL) was added dropwise 30%
H.sub.2O.sub.2 (10 mL) at 0.degree. C. After the dropwise addition
was completed, the mixture was stirred at 25.degree. C. for 10 h,
and then diluted with water (50 mL). The aqueous layer was
extracted with EtOAc (100 mL.times.2). The combined organic layers
were washed with water (50 mL.times.2), brine (50 mL.times.2),
dried over Na.sub.2SO.sub.4, filtered and evaporated. The residue
was purified by column chromatography to provide the title compound
as yellow solids (270 g, yield: 68%). LCMS (ESI) m/z: 432
(M+1).
Example 109E
6-fluoro-3-(4-(hydroxymethyl)piperidin-4-yl)-4H-benzo[4,5]imidazo[1,2-b]py-
razole-8-carboxamide
##STR00287##
A mixture of EXAMPLE 109D (100 g, 0.23 mmol) in DCM (10 mL) and TFA
(3 mL) was stirred at 25.degree. C. for 3 h. The resultant mixture
was evaporated to give the title compound as yellow oil which could
be used directly in the next step without further purification.
LCMS (ESI) m/z: 332 (M+1).
Example 109F
3-(1-(cyclopropylmethyl)-4-(hydroxymethyl)piperidin-4-yl)-6-fluoro-4H-benz-
o[4,5]imidazo[1,2-b]pyrazole-8-carboxamide
##STR00288##
This example was prepared as the method described in Example 108E.
.sup.1H-NMR (400 MHz, DMSO-d.sub.6+D.sub.2O) .delta. ppm 0.06-0.35
(m, 2H), 0.44-0.70 (m, 2H), 0.81-1.14 (m, 1H), 1.57-2.01 (m, 1H),
2.05-2.47 (m, 1H), 2.57-2.98 (m, 1H), 3.08-3.28 (m, 1H), 3.32-3.52
(m, 1H), 7.38-7.69 (m, 2H), 7.80 (s, 1H), 8.34 (s, 1H). LCMS (ESI)
m/z: 386 (M+1).
Example 110
methyl
4-(8-carbamoyl-6-fluoro-4H-benzo[4,5]imidazo[1,2-b]pyrazol-3-yl)-1--
(cyclopropylmethyl)piperidine-4-carboxylate
##STR00289##
Example 110A
1-(tert-butyl) 4-methyl
4-(8-bromo-6-fluoro-4H-benzo[4,5]imidazo[1,2-b]pyrazol-3-yl)piperidine-1,-
4-dicarboxylate
##STR00290##
A solution of EXAMPLE 109A (250 g, 0.52 mmol) in a mixture of
MeOH/DCM=10/1 (1 mL) was added dropwise TMSCH.sub.2N.sub.2 (0.52
mL, 1.04 mmol) at 0.degree. C. under N.sub.2 atmosphere. After
being stirred at 0.degree. C. for 5 min, the reaction solution was
quenched with HOAc/H.sub.2O=1/10 (20 mL). The aqueous layer was
extracted with CH.sub.2Cl.sub.2 (50 mL.times.2). The combined
organic layers were washed with brine, dried over Na.sub.2SO.sub.4,
filtered and evaporated. The residue was purified by column
chromatograph to provide the title compound (200 g, yield: 78%).
LCMS (ESI) m/z: 495, 497 (M, M+2).
Example 110B
methyl
4-(8-carbamoyl-6-fluoro-4H-benzo[4,5]imidazo[1,2-b]pyrazol-3-yl)-1--
(cyclopropylmethyl)piperidine-4-carboxylate
##STR00291##
This example was prepared as the method described in Examples
109C-109F. (11 g, yield: 37%). LCMS (ESI) m/z: 414 (M+1).
.sup.1H-NMR (400 MHz, MethanoL-d4) .delta. ppm 0.34 (d, J=5.90 Hz,
2H), 0.67-0.75 (m, 2H), 0.99-1.13 (m, 1H), 2.37 (br. s., 2H), 2.58
(br. s., 2H), 2.75 (d, J=6.90 Hz, 2H), 2.89-3.07 (m, 2H), 3.39-3.61
(m, 2H), 7.44 (dd, J=8.09, 2.57 Hz, 1H), 7.75 (dd, J=10.85, 2.57
Hz, 1H), 7.90 (s, 1H), 8.34-8.47 (m, 1H). LCMS (ESI) m/z: 414
(M+1).
##STR00292##
Example 111
3-(1-(cyclopropylmethyl)-4-methylpiperidin-4-yl)-6-fluoro-2-methyl-4H-benz-
o[4,5]imidazo[1,2-b]pyrazole-8-carboxamide
##STR00293##
Example 111A
tert-butyl
4-(1-cyano-2-oxopropyl)-4-methylpiperidine-1-carboxylate
##STR00294##
To a solution of EXAMPLE 53C (5.0 g, 21.0 mmol) in dry THF (60 mL)
was added dropwise LDA (26 mL, 52.0 mmol) at -78.degree. C. under
N.sub.2 atmosphere, followed by dropwise addition of Ac.sub.2O (5.4
g, 52.0 mmol) after stirring at -78.degree. C. for 1 h. The
resultant mixture was slowly warmed to room temperature and stirred
for 30 min. The mixture was quenched with sat aq NH.sub.4Cl
solution (30 mL). The aqueous layer was extracted with EtOAc (30
mL.times.2). The combined organic layers were evaporated and the
residue was purified by column chromatograph to provide the title
compound (4.5 g, yield: 76.5%) as yellow oil. LCMS (ESI) m/z: 281
(M+1).
Example 111B
tert-butyl-4-(1-cyano-2-(2-(2,6-dibromo-4-fluorophenyl)hydrazono)propyl)-4-
-methylpiperidine-1-carboxylate
##STR00295##
A mixture of EXAMPLE 111A (2.0 g, 7.14 mmol), HOAc (0.2 mL) and
EXAMPLE 1D (2.4 g, 8.57 mmol) in EtOH (30 mL) was stirred at
70.degree. C. for 16 h. After removal of solution in vacuum, the
residue was purified by column chromatograph to provide the title
compound (2.1 g, yield: 53.8%) as a light yellow solid.
Example 111C
tert-butyl
4-(5-amino-1-(2,6-dibromo-4-fluorophenyl)-3-methyl-1H-pyrazol-4-
-yl)-4-methylpiperidine-1-carboxylate
##STR00296##
A mixture of EXAMPLE 111B (2.1 g, 3.84 mmol) and K.sub.2CO.sub.3
(2.1 g, 15.4 mmol) in EtOH (30 mL) was heated to 80.degree. C. and
stirred for 4 h. After removal of solution in vacuum, the residue
was purified by column chromatograph to provide the title compound
(0.8 g, yield: 54.4%) as a light red solid.
Example 111D
tert-butyl
4-(8-bromo-6-fluoro-2-methyl-4H-benzo[4,5]imidazo[1,2-b]pyrazol-
-3-yl)-4-methylpiperidine-1-carboxylate
##STR00297##
A mixture of EXAMPLE 111C (700 g, 1.28 mmol), CuI (73 g, 0.38
mmol), K.sub.3PO.sub.4 (814 g, 3.84 mmol) and N,
N-dimethyl-1,2-ethane-1,2-diamine (68 g, 0.76 mmol) in DMF (15 mL)
was stirred at 70.degree. C. for 5 h under N.sub.2 atmosphere.
After being cooled to room temperature, the mixture was filtered
and the filtrate was concentrated in vacuum. The residue was
purified by column chromatograph to provide the title compound (400
g, yield: 67.0%) as a yellow solid. LCMS (ESI) m/z: 465, 467 (M,
M+2).
Example 111E
tert-butyl
4-(8-cyano-6-fluoro-2-methyl-4H-benzo[4,5]imidazo[1,2-b]pyrazol-
-3-yl)-4-methylpiperidine-1-carboxylate
##STR00298##
A mixture of EXAMPLE 111D (650 g, 1.39 mmol), Zn(CN).sub.2 (326 g,
2.78 mmol), Pd.sub.2(dba).sub.3 (254 mg, 0.28 mmol), DPPF (309 g,
0.56 mmol) and Zn (181 g, 2.78 mmol) in DMF (8 mL) was stirred at
120.degree. C. for 3 h under N.sub.2 atmosphere. After being cooled
to room temperature, the resultant mixture was filtered and
concentrated in vacuum. The residue was purified by column
chromatography to provide the title compound (450 g, yield: 78.5%)
as yellow solids. LCMS (ESI) m/z: 412 (M+1).
Example 111F
tert-butyl
4-(8-carbamoyl-6-fluoro-2-methyl-4H-benzo[4,5]imidazo[1,2-b]pyr-
azol-3-yl)-4-methylpiperidine-1-carboxylate
##STR00299##
To a mixture of EXAMPLE 111E (450 g, 1.09 mmol) and K.sub.2CO.sub.3
(906 g, 6.56 mmol) in DMSO (10 mL) was added 30% H.sub.2O.sub.2 (6
mL) at 0.degree. C. After the dropwise addition was completed, the
mixture was stirred at 25.degree. C. for 16 h, and then diluted
with water (50 mL). The aqueous phase was extracted with EtOAc (50
mL.times.2). The combined organic layers were washed with sat
Na.sub.2SO.sub.3 aq solution (50 mL.times.2), brine (100 mL), dried
over Na.sub.2SO.sub.4, filtered and evaporated. The residue was
purified by column chromatograph to provide the title compound (450
g, yield: 95.7%) as a white solids. LCMS (ESI) m/z: 430 (M+1).
Example 111G
3-(1-(cyclopropylmethyl)-4-methylpiperidin-4-yl)-6-fluoro-2-methyl-4H-benz-
o[4,5]imidazo[1,2-b]pyrazole-8-carboxamide
##STR00300##
This example was prepared as described in Examples 109E and 109F.
(50 g, yield: 56.2%). .sup.1H-NMR (400 MHz, MethanoL-d.sub.4)
.delta. ppm 0.41 (d, J=4.52 Hz, 2H), 0.64-0.83 (m, 2H), 1.12 (br.
s., 1H), 1.47 (br. s., 3H), 2.09 (br. s., 2H), 2.50 (s, 3H),
2.54-2.71 (m, 2H), 2.84-3.29 (m, 4H), 3.52 (br. s., 2H), 7.28 (d,
J=8.03 Hz, 1H), 7.48-7.69 (m, 1H), 8.63 (br. s., 1H). LCMS (ESI)
m/z: 384 (M+1).
Example 112
3-(1-ethyl-4-methylpiperidin-4-yl)-6-fluoro-2-methyl-4H-benzo[4,5]imidazo[-
1,2-b]pyrazole-8-carboxamide
##STR00301##
This example was prepared as the method described in Example 111.
.sup.1H-NMR (400 MHz, MethanoL-d.sub.4) .delta. ppm 1.20-1.61 (m,
6H), 2.09 (br. s., 2H), 2.49 (s, 3H), 2.52-2.77 (m, 2H), 3.17 (br.
s., 4H), 3.49 (br. s., 2H), 7.16-7.34 (m, 1H), 7.46-7.63 (m, 1H),
8.46 (s, 1H). LCMS (ESI) m/z: 358 (M+1).
Example 113
6-fluoro-3-(1-isobutyl-4-methylpiperidin-4-yl)-2-methyl-4H-benzo[4,5]imida-
zo[1,2-b]pyrazole-8-carboxamide
##STR00302##
This example was prepared as the method described in Example 111.
.sup.1H NMR (400 MHz, DMSO-d.sub.6) 0.84 (d, J=6.5 Hz, 7H), 1.26
(s, 3H), 1.76 (d, J=6.8 Hz, 3H), 2.00 (d, J=7.3 Hz, 2H), 2.13-2.29
(m, 3H), 2.34 (s, 1H), 2.41 (s, 3H), 2.68 (s, 1H), 7.36 (dd, J=2.5,
8.3 Hz, 1H), 7.55 (dd, J=2.5, 11.0 Hz, 1H), 8.04 (s, 1H), 8.29 (br,
s, 1H), 10.63 (s, 1H). LCMS (ESI) m/z: 386 (M+1).
Example 114
6-fluoro-3-(1-isopropyl-4-methylpiperidin-4-yl)-2-methyl-4H-benzo[4,5]imid-
azo[1,2-b]pyrazole-8-carboxamide
##STR00303##
This example was prepared as the method described in Example 111.
.sup.1H-NMR (400 MHz, MethanoL-d.sub.4) .delta. ppm 1.34 (d, J=5.52
Hz, 6H), 1.47 (br. s., 3H), 2.11 (br. s., 2H), 2.51 (s, 3H),
2.53-2.72 (m, 2H), 3.11 (br. s., 2H), 3.44 (br. s., 3H), 7.20-7.38
(m, 1H), 7.59 (dd, J=10.92, 2.64 Hz, 1H), 8.66 (br. s., 1H). LCMS
(ESI) m/z: 372 (M+1).
Example 115
3-(1,4-dimethylpiperidin-4-yl)-6-fluoro-2-methyl-4H-benzo[4,5]imidazo[1,2--
b]pyrazole-8-carboxamide
##STR00304##
This example was prepared as the method described in Example 111.
.sup.1H-NMR (400 MHz, MethanoL-d.sub.4) .delta. ppm 1.46 (s, 3H),
2.05 (br. s., 2H), 2.50 (s, 3H), 2.56 (d, J=11.67 Hz, 2H), 2.79 (s,
3H), 3.09 (br. s., 2H), 3.34-3.41 (m, 2H), 7.31 (dd, J=8.09, 2.32
Hz, 1H), 7.63 (dd, J=10.98, 2.20 Hz, 1H), 8.55 (s, 1H). LCMS (ESI)
m/z: 344 (M+1).
Example 116
6-fluoro-3-(1-(2-hydroxy-2-methylpropyl)-4-methylpiperidin-4-yl)-2-methyl--
4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide
##STR00305##
This example was prepared as the method described in Example 111.
.sup.1H NMR (400 MHz, DMSO-d.sub.6) 1.02-1.14 (m, 6H), 1.26 (s,
3H), 1.69-1.81 (m, 2H), 2.11-2.24 (m, 4H), 2.32-2.44 (m, 6H), 2.68
(br, s, 2H), 7.37 (dd, J=2.5, 8.3 Hz, 1H), 7.56 (dd, J=2.5, 11.0
Hz, 1H), 8.06 (s, 1H), 8.28 (s, 1H), 10.65 (s, 1H). LCMS (ESI) m/z:
402 (M+1).
Example 117
3-(1-ethyl-2,4-dimethylpiperidin-4-yl)-6-fluoro-2-methyl-4H-benzo[4,5]imid-
azo[1,2-b]pyrazole-8-carboxamide
##STR00306##
This example was prepared as the method described in Example 111.
.sup.1H NMR (400 MHz, DMSO-d.sub.6) 1.07 (t, J=7.0 Hz, 3H), 1.13
(d, J=6.0 Hz, 3H), 1.41 (s, 3H), 1.84-1.72 (m, 1H), 1.97 (d, J=10.8
Hz, 2H), 2.05-2.16 (m, 1H), 2.44 (s, 3H), 2.54-2.70 (m, 2H), 2.77
(br, s, 1H), 2.90-3.03 (m, 2H), 7.41 (dd, J=2.4, 8.4 Hz, 1H), 7.55
(dd, J=2.5, 11.0 Hz, 1H), 8.05 (s, 1H), 8.33 (s, 1H), 10.63 (s,
1H). LCMS (ESI) m/z: 372 (M+1).
Example 118
3-(1-ethyl-3-methylpyrrolidin-3-yl)-6-fluoro-2-methyl-4H-benzo[4,5]imidazo-
[1,2-b]pyrazole-8-carboxamide
##STR00307##
This example was prepared as the method described in Example 111.
.sup.1H-NMR (MeOD, 400 MHz) .delta.: 1.37-1.41 (t, 3H), 1.58 (s,
3H), 2.47-2.49 (m, 1H), 2.51 (s, 3H), 2.67-2.74 (m, 1H), 3.29-3.30
(m, 2H), 3.34-3.67 (m, 4H), 7.33-7.35 (d, 1H), 7.66-7.69 (d, 1H),
8.52 (bs, 1H). LCMS (ESI) m/z: 344 (M+1).
Example 119
6-fluoro-3-(1-isopropyl-3-methylpyrrolidin-3-yl)-2-methyl-4H-benzo[4,5]imi-
dazo[1,2-b]pyrazole-8-carboxamide
##STR00308##
This example was prepared as the method described in Example 111.
.sup.1H-NMR (MeOD, 400 MHz) .delta.: 1.36-1.45 (m, 6H), 1.52-1.59
(m, 3H), 2.48 (s, 4H), 2.61-2.73 (m, 1H), 3.45-3.53 (m, 1H),
3.55-3.82 (m, 4H), 7.24-7.33 (m, 1H), 7.56-7.68 (m, 1H), 8.40-8.55
(bs, 1H). LCMS (ESI) m/z: 358 (M+1).
Example 120
3-(1-(cyclopropylmethyl)-3-methylpyrrolidin-3-yl)-6-fluoro-2-methyl-4H-ben-
zo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide
##STR00309##
This example was prepared as the method described in Example 111.
.sup.1H-NMR (MeOD, 400 MHz) .delta.: 0.59 (d, 2H), 0.96-1.06 (m,
1H), 1.53 (s, 3H), 2.12-2.22 (m, 1H), 2.48 (s, 5H), 2.83-2.94 (m,
1H), 2.98-3.08 (m, 2H), 3.11-3.20 (m, 1H), 7.33-7.36 (m, 1H),
7.61-7.74 (m, 1H). LCMS (ESI) m/z: 370 (M+1).
Example 121
3-(1,3-dimethylazetidin-3-yl)-6-fluoro-2-methyl-4H-benzo[4,5]imidazo[1,2-b-
]pyrazole-8-carboxamide
##STR00310##
This example was prepared as the method described in Example 111.
.sup.1H-NMR (400 MHz, MethanoL-d.sub.4) .delta. ppm 1.74 (s, 3H),
2.37 (s, 3H), 2.94 (s, 3H), 4.27 (d, J=9.79 Hz, 2H), 4.43 (d,
J=9.29 Hz, 2H), 7.29 (d, J=8.28 Hz, 1H), 7.62 (d, J=10.92 Hz, 1H),
8.51 (br. s., 1H). LCMS (ESI) m/z: 316 (M+1).
Example 122
3-(1-ethyl-3-methylazetidin-3-yl)-6-fluoro-2-methyl-4H-benzo[4,5]imidazo[1-
,2-b]pyrazole-8-carboxamide
##STR00311##
This example was prepared as the method described in Example 111.
.sup.1H-NMR (MeOD, 400 MHz) .delta.: 1.01-1.08 (m, 3H), 1.65-1.70
(m, 3H), 2.34 (s, 3H), 2.55-2.65 (m, 2H), 3.47-3.53 (m, 2H),
3.59-3.66 (m, 2H), 7.28-7.36 (dd, 1H), 7.63-7.73 (dd, 1H). LCMS
(ESI) m/z: 330 (M+1).
Example 123
6-fluoro-3-(1-isopropyl-3-methylazetidin-3-yl)-2-methyl-4H-benzo[4,5]imida-
zo[1,2-b]pyrazole-8-carboxamide
##STR00312##
This example was prepared as the method described in Example 111.
.sup.1H-NMR (MeOD, 400 MHz) .delta.: 1.26 (d, J=6.53 Hz, 6H), 1.75
(s, 3H), 2.40 (s, 3H), 3.38 (d, J=5.90 Hz, 1H), 4.20-4.28 (m, 2H),
4.33-4.44 (m, 2H), 7.27-7.43 (dd, 1H), 7.62-7.76 (dd, 1H),
8.43-8.58 (bs, 1H). LCMS (ESI) m/z: 344 (M+1).
Example 124
3-(1-(cyclopropylmethyl)-3-methylazetidin-3-yl)-6-fluoro-2-methyl-4H-benzo-
[4,5]imidazo[1,2-b]pyrazole-8-carboxamide
##STR00313##
This example was prepared as the method described in Example 111.
.sup.1H-NMR (400 MHz, MethanoL-d.sub.4) .delta. ppm 0.46 (d, J=4.02
Hz, 2H), 0.66-0.82 (m, 2H), 1.09 (d, J=6.02 Hz, 1H), 1.76 (s, 3H),
2.37 (s, 3H), 3.19 (br. s., 2H), 4.19-4.40 (m, 2H), 4.54 (d, J=9.16
Hz, 2H), 7.24 (br. s., 1H), 7.57 (br. s., 1H), 8.53 (br. s., 1H).
LCMS (ESI) m/z: 356 (M+1).
Example 125
6-fluoro-3-(1-(2-hydroxy-2-methylpropyl)-3-methylazetidin-3-yl)-2-methyl-4-
H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxamide
##STR00314##
This example was prepared as the method described in Example 111.
.sup.1H-NMR (400 MHz, MethanoL-d.sub.4) .delta. ppm 1.32 (s, 6H),
1.75 (s, 3H), 2.30-2.43 (m, 3H), 3.24 (s, 2H), 4.35 (d, J=9.91 Hz,
2H), 4.52 (d, J=9.29 Hz, 2H), 7.26 (d, J=8.03 Hz, 1H), 7.61 (d,
J=11.04 Hz, 1H), 8.50 (br. s., 1H). LCMS (ESI) m/z: 374 (M+1).
Example 126
6-fluoro-3-(1-isopropyl-4-methylpiperidin-4-yl)-2-methoxy-4H-benzo[4,5]imi-
dazo[1,2-b]pyrazole-8-carboxamide
##STR00315##
Example 126A
tert-butyl
4-(1-cyano-2-(2-(2,6-dibromo-4-fluorophenyl)hydrazinyl)-2-oxoet-
hyl)-4-methylpiperidine-1-carboxylate
##STR00316##
A mixture of EXAMPLE 105C (2.73 g, crude, 9.67 mmol), HATU (5.51 g,
0.26 mmol), EXAMPLE 1D (3.29 g, 11.60 mmol) and Et.sub.3N (2.84 g,
29.01 mmol) in DMF (20 mL) was stirred at 25.degree. C. for 10 h
under N.sub.2 atmosphere. After completion the reaction mixture was
quenched with water (100 mL) and extracted with EtOAc (100
mL.times.2). The combined organic layers were washed with water (50
mL.times.2) and brine (50 mL.times.2), dried over Na.sub.2SO.sub.4,
filtered and evaporated. The residue was purified by column
chromatograph to provide the title compound (4.50 g, yield: 85%) as
yellow solids.
Example 126B
tert-butyl
4-(5-amino-1-(2,6-dibromo-4-fluorophenyl)-3-hydroxy-1H-pyrazol--
4-yl)-4-methylpiperidine-1-carboxylate
##STR00317##
A mixture of EXAMPLE 126A (4.50 g, 8.21 mmol) and K.sub.2CO.sub.3
(2.27 g, 16.42 mmol) in ethanol (100 mL) was stirred at 80.degree.
C. for 15 h. After removal of solution in vacuum, the residue was
diluted with water (100 mL). The aqueous layer was extracted with
EtOAc (100 mL.times.2). The combined organic layers were washed
with water (50 mL.times.2) and brine (50 mL.times.2), dried over
Na.sub.2SO.sub.4, filtered and evaporated. The residue was purified
by column chromatograph to provide the title compound (3.81 g,
yield: 84%) as a yellow solid.
Example 126C
tert-butyl
4-(5-amino-1-(2,6-dibromo-4-fluorophenyl)-3-methoxy-1H-pyrazol--
4-yl)-4-methylpiperidine-1-carboxylate
##STR00318##
A mixture of EXAMPLE 126B (2.3 g, 3.65 mmol), MeI (517.80 g, 3.65
mmol) and K.sub.2CO.sub.3 (1.51 g, 10.94 mmol) in DMF (50 ml) was
stirred at 25.degree. C. for 15 h. After removal of solution in
vacuum, the residue was diluted with water (100 mL). The aqueous
layer was extracted with EtOAc (100 mL.times.2). The combined
organic layers were washed with water (50 mL.times.2), brine (50
mL.times.2), dried over Na.sub.2SO.sub.4, filtered and evaporated.
The residue was purified by column chromatograph to provide the
title compound (590 g, yield: 28.76%) as a yellow solid.
Example 126D
tert-butyl
4-(8-bromo-6-fluoro-2-methoxy-4H-benzo[4,5]imidazo[1,2-b]pyrazo-
l-3-yl)-4-methylpiperidine-1-carboxylate
##STR00319##
A mixture of EXAMPLE 126C (680 g, 1.21 mmol), CuI (69 g, 0.36
mmol), N.sup.1,N.sup.2-dimethylethane-1,2-diamine (64 g, 0.73 mmol)
and K.sub.3PO.sub.4 (770 g, 3.63 mmol) in DMF (15 mL) was stirred
at 70.degree. C. for 10 h under N.sub.2 atmosphere. After being
cooled to room temperature, the resultant mixture was filtered and
the filtrate was evaporated. The residue was purified by column
chromatography to provide the title compound (455 g, yield: 78%) as
white solids. LCMS (ESI) m/z: 481, 483 (M, M+2).
Example 126E
tert-butyl
4-(8-cyano-6-fluoro-2-methoxy-4H-benzo[4,5]imidazo[1,2-b]pyrazo-
l-3-yl)-4-methylpiperidine-1-carboxylate
##STR00320##
A mixture of EXAMPLE 126D (400 g, 0.83 mmol), Zn(CN).sub.2 (108 g,
1.69 mmol), Pd.sub.2(dba).sub.3 (152 mg, 0.16 mmol), DPPF (185 g,
0.33 mmol) and Zn (108 g, 1.66 mmol) in DMF (8 mL) was stirred at
120.degree. C. for 15 h under N.sub.2 atmosphere. After being
cooled to room temperature, the resultant mixture was filtered and
the filtrate was evaporated. The residue was purified by column
chromatography to provide the title compound (330 g, yield: 81%) as
yellow solids. LCMS (ESI) m/z: 428 (M+1).
Example 126F
tert-butyl
4-(8-carbamoyl-6-fluoro-2-methoxy-4H-benzo[4,5]imidazo[1,2-b]py-
razol-3-yl)-4-methylpiperidine-1-carboxylate
##STR00321##
To a mixture of EXAMPLE 126E (200 g, 0.47 mmol) and K.sub.2CO.sub.3
(300 g, 2.17 mmol) in DMSO (5 mL) was added 30% H.sub.2O.sub.2 (5
mL) at 0.degree. C. After being stirred at 25.degree. C. for 15 h,
the mixture was diluted with water (50 mL). The aqueous layer was
extracted with EtOAc (50 mL.times.3). The combined organic layers
were washed with water (50 mL) and brine (50 mL), dried over
Na.sub.2SO.sub.4, filtered and evaporated. The residue was purified
by column chromatography to provide the title compound (195 g,
yield: 93%) as white solids. LCMS (ESI) m/z: 446 (M+1).
Example 126G
6-fluoro-2-methoxy-3-(4-methylpiperidin-4-yl)-4H-benzo[4,5]imidazo[1,2-b]p-
yrazole-8-carboxamide
##STR00322##
A solution of EXAMPLE 126F (100 g, 0.22 mmol) in a mixture of
DCM/TFA (10 mL/3 mL) was stirred at 25.degree. C. for 3 h. After
removal of solution in vacuum, the title compound was provided and
used directly in the next step without further purification.
Example 126H
6-fluoro-3-(1-isopropyl-4-methylpiperidin-4-yl)-2-methoxy-4H-benzo[4,5]imi-
dazo[1,2-b]pyrazole-8-carboxamide
##STR00323##
A mixture of EXAMPLE 126G (78 g, crude, 0.22 mmol), acetone (70 g,
1.2 mmol) and Na(CN)BH.sub.3 (140 g, 2.22 mmol) in a mixture of
THF/MeOH (15 mL/5 mL) was stirred at 24.degree. C. for 15 h. The
mixture was diluted with water (20 mL). The aqueous layer was
extracted with EtOAc (30 mL.times.2). The combined organic layers
were washed with water (20 mL) and brine (20 mL), dried over
Na.sub.2SO.sub.4, filtered and evaporated. The residue was purified
by prep-HPLC to provide the title compound (35 g, yield: 41%) as a
white solid. .sup.1H-NMR (400 MHz, MethanoL-d.sub.4) .delta. ppm
1.27-1.52 (m, 9H), 1.77-2.19 (m, 2H), 2.69 (br. s., 2H), 2.84-3.28
(m, 2H), 3.39-3.55 (m, 3H), 4.06 (s, 3H), 7.31 (dd, J=8.03, 2.51
Hz, 1H), 7.66 (dd, J=10.98, 2.45 Hz, 1H), 8.55 (br. s., 1H). LCMS
(ESI) m/z: 388 (M+1).
Example 127
2-(benzyloxy)-6-fluoro-3-(1-isopropyl-4-methylpiperidin-4-yl)-4H-benzo[4,5-
]imidazo[1,2-b]pyrazole-8-carboxamide
##STR00324##
Example 127A
##STR00325##
A mixture of EXAMPLE 126B (3.0 g, 5.48 mmol), Boc.sub.2O (10.0 g,
45.8 mmol) and DMAP (670 g, 5.48 mmol) was stirred at 80.degree. C.
for 3 hours. After being cooled to room temperature, the mixture
was diluted with aq NaHCO.sub.3 solution (30 mL). The aqueous layer
was extracted with DCM (100 mL.times.3). The combined organic
layers were dried over Na.sub.2SO.sub.4, filtered and evaporated to
provide the title compound (4.5 g crude) which could be used
directly in the next step without further purification.
Example 127B
##STR00326##
A mixture of EXAMPLE 127A (4.5 g, 5.31 mmol) and K.sub.2CO.sub.3
(1.46 g, 10.62 mmol) in MeOH (40 mL) was stirred at 20.degree. C.
for 4 h. The mixture was filtered and the filtrate was evaporated.
The residue was purified by chromatography to provide the title
compound (3.1 g, yield: 80%) as a yellow solid.
Example 127C
##STR00327##
A mixture of EXAMPLE 127B (2.5 g, 3.35 mmol), K.sub.2CO.sub.3 (925
g, 6.7 mmol) and BnBr (626 g, 3.68 mmol) in MeOH (30 mL) was
stirred at 60.degree. C. for 8 h. The mixture was filtered and the
filtrate was evaporated. The residue was purified by chromatography
to provide the title compound (1.4 g crude) as a white solid.
Example 127D
3-(benzyloxy)-1-(2,6-dibromo-4-fluorophenyl)-4-(4-methylpiperidin-4-yl)-1H-
-pyrazol-5-amine
##STR00328##
A solution of EXAMPLE 127C (1.4 g, 1.63 mmol) in 4M HCl/EtOAc (20
mL) was stirred at 10.degree. C. for 3 hours. After removal of
solution in vacuum, the title compound was provided (1.0 g, yield:
100%) as a yellow solid and used directly in the next step without
further purification.
Example 127E
tert-butyl
4-(5-amino-3-(benzyloxy)-1-(2,6-dibromo-4-fluorophenyl)-1H-pyra-
zol-4-yl)-4-methylpiperidine-1-carboxylate
##STR00329##
A mixture of EXAMPLE 127D (1.0 g, 1.78 mmol), Et.sub.3N (362 g,
3.56 mmol) and Boc.sub.2O (776 g, 3.56 mmol) in DCM (15 mL) was
stirred at 10.degree. C. for 4 hours. The mixture was diluted with
H.sub.2O (20 mL). The aqueous layer was extracted with DCM (15
mL.times.2). The combined organic layers were washed with water,
brine, dried over Na.sub.2SO.sub.4, filtered and evaporated. The
residue was purified by column chromatograph to provide the title
compound (1.0 g crude) as a white solid.
Example 127F
2-(benzyloxy)-6-fluoro-3-(1-isopropyl-4-methylpiperidin-4-yl)-4H-benzo[4,5-
]imidazo[1,2-b]pyrazole-8-carboxamide
##STR00330##
This example was prepared as described in Examples 126D-126H.
.sup.1H NMR (400 MHz, DMSO-d.sub.6) 0.95 (d, J=6.5 Hz, 6H), 1.24
(s, 3H), 1.60-1.72 (m, 2H), 2.34 (br, s, 4H), 2.66-2.77 (m, 3H),
5.32 (s, 2H), 7.29-7.55 (m, 7H), 8.04 (s, 1H), 8.34 (br, s, 1H),
10.20 (s, 1H). LCMS (ESI) m/z: 464 (M+1).
##STR00331##
Example 128
6-fluoro-2-(piperidin-4-yl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxam-
ide
##STR00332##
Example 128A
tert-butyl 4-(2-cyanoacetyl)piperidine-1-carboxylate
##STR00333##
To a solution of acetonitrile (5.06 g, 123.4 mmol) in dry THF (200
mL) was added n-BuLi (39.5 mL, 98.6 mmol) dropwise at -78.degree.
C. under nitrogen atmosphere. The mixture was stirred at
-78.degree. C. for 2 h. Thereafter, a solution of 1-(tert-butyl)
4-methyl piperidine-1,4-dicarboxylate (20 g, 82.2 mmol) in
tetrahydrofuran (100 mL) was added dropwise into the above mixture.
After the dropwise addition was completed, the resultant mixture
was warmed to 15.degree. C. and stirred for 16 h and subsequently
quenched with sat aq NH.sub.4Cl solution (100 mL). The aqueous
phase was extracted with EtOAc (100 mL.times.2). The combined
organic layers were dried over Na.sub.2SO.sub.4, filtered and
evaporated. The residue was purified by column chromatograph to
provide the title compound (7.9 g, yield: 38.1%) as a yellow solid.
LCMS (ESI) m/z: 253 (M+1).
Example 128B
tert-butyl-4-(2-cyano-1-(2-(2,6-dibromo-4-fluorophenyl)hydrazono)ethyl)pip-
eridine-1-carboxylate
##STR00334##
A mixture of EXAMPLE 128A (6.35 g, 25.16 mmol) and EXAMPLE 1D (10
g, 35.2 mmol) in ethanol (80 mL) and HOAc (80 mL) was stirred at
85.degree. C. for 16 h. After being cooled to room temperature, the
mixture was evaporated to provide the title compound (15 g, crude)
which could be used directly in the next step with out further
purification.
Example 128C
tert-butyl
4-(5-amino-1-(2,6-dibromo-4-fluorophenyl)-1H-pyrazol-3-yl)piper-
idine-1-carboxylate
##STR00335##
A mixture of EXAMPLE 128B (13 g, 25.1 mmol) and Et.sub.3N (12.7 g,
125.5 mmol) in ethanol (100 mL) was heated to 80.degree. C. for
about 16 h. After being cooled to room temperature, the mixture was
evaporated. The residue was purified by column chromatograph to
provide the title compound (11 g, yield: 84.6%) as a yellow
solid.
Example 128D
tert-butyl
4-(8-bromo-6-fluoro-4H-benzo[4,5]imidazo[1,2-b]pyrazol-2-yl)pip-
eridine-1-carboxylate
##STR00336##
A mixture of EXAMPLE 128C (1.5 g, 2.9 mmol), CuI (166 g, 0.87
mmol), K.sub.3PO.sub.4 (1.8 g, 8.7 mmol) and
N.sup.1,N.sup.2-dimethylethane-1,2-diamine (153 g, 1.74 mmol) in
DMF (8 mL) was stirred at 55.degree. C. for 18 h under N.sub.2
atmosphere. After being cooled to room temperature, the resultant
mixture was diluted with water (20 mL). The aqueous layer was
extracted with EtOAc (20 mL.times.2). The combined organic layers
were washed with water (20 mL), brine (20 mL), dried over
Na.sub.2SO.sub.4, filtered and evaporated. The residue was purified
by column chromatograph to provide the title compound (350 g,
yield: 27.6%) as a yellow solid. LCMS (ESI) m/z: 437, 439 (M,
M+2).
Example 128E
tert-butyl
4-(8-carbamoyl-6-fluoro-4H-benzo[4,5]imidazo[1,2-b]pyrazol-2-yl-
)piperidine-1-carboxylate
##STR00337##
A mixture of EXAMPLE 128D (350 g, 0.8 mmol), Zn(CN).sub.2 (188 g,
1.6 mmol), Pd.sub.2(dba).sub.3 (110 g, 0.12 mmol), DPPF (133 g,
0.24 mmol), and Zn powder (104 g, 1.6 mmol) in DMF (4 mL) was
stirred at 120.degree. C. for 2 h under N.sub.2 atmosphere. After
being cooled to room temperature, the resultant mixture was
filtered and the filtrate was evaporated. The residue was purified
by prep-TLC to provide the title compound (50 g, yield: 16.2%) as a
yellow solid. LCMS (ESI) m/z: 402 (M+1).
Example 128F
6-fluoro-2-(piperidin-4-yl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-carboxam-
ide
##STR00338##
A mixed solution of EXAMPLE 128E (50 g, 0.125 mmol) in TFA (1 mL)
and DCM (6 mL) was stirred at 20.degree. C. for 2 h. The resultant
mixture was evaporated. The residue was purified by prep-HPLC to
provide the title compound (23 g, yield: 59.0%) as a white solid.
.sup.1H-NMR (400 MHz, MethanoL-d.sub.4) .delta. ppm 1.07-1.27 (m,
9H), 2.51 (d, J=1.51 Hz, 2H), 2.76-2.97 (m, 2H), 3.34 (d, J=3.26
Hz, 2H), 5.74 (br. s., 1H), 7.36.about.7.39 (m, 1H),
7.68.about.7.72 (m, 1H). LCMS (ESI) m/z: 302 (M+1).
Example 129
2-(1-ethylpiperidin-4-yl)-6-fluoro-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8-c-
arboxamide
##STR00339##
A mixture of EXAMPLE 128F (20 g, 0.066 mmol), 40% acetaldehyde (0.2
mL) and Na(CN)BH.sub.3 (17 mg, 0.264 mmol) in MeOH (5 mL) was
stirred at 10.degree. C. for 16 h. After the reaction was complete,
the resultant mixture was diluted with water (5 mL). The aqueous
layer was extracted with DCM (20 mL.times.2). The combined organic
layers were evaporated. The residue was purified by prep-HPLC to
provide the title compound (17.36 g, yield: 78.9%) as a light
yellow solid. .sup.1H-NMR (400 MHz, MethanoL-d.sub.4) .delta. ppm
1.38 (t, J=7.28 Hz, 3H), 1.98-2.23 (m, 2H), 2.28-2.49 (m, 2H),
2.92-3.25 (m, 5H), 3.57 (d, J=11.54 Hz, 2H), 5.83 (s, 1H), 7.29
(dd, J=8.28, 2.51 Hz, 1H), 7.61 (dd, J=10.92, 2.51 Hz, 1H), 8.60
(br. s., 1H). LCMS (ESI) m/z: 330 (M+1).
In Vitro Studies
Cellular PARylation Assay
HCC1937 cells were planted into 96 well plates at 4.times.10.sup.4
cells/well and incubated at 37.degree. C. in an incubator
overnight. After being treated with a test compound for 30 min,
cells were then treated with 1 mM H.sub.2O.sub.2 for 10 min. The
cells were washed with 200 ul pre-chilled PBS twice and fixed with
100 ul pre-chilled methanol/acetone (7:3) on ice for 30 min. After
being air-dried, the plates were blocked using PBS-Tween blocking
solution (0.05%) with dissolved 5% nonfat dry milk for 30 min at
room temperature. The cells were incubated with anti-PAR antibody
10H (1:100) at room temperature for 1 hour followed by washing with
PBS-Tween20 for 3 times; and then added into a blocking solution
including goat anti-mouse fluorescein isothiocyanate (FITC)-coupled
secondary antibody and 1 .mu.g/mL DAPI to incubate away from light
at room temperature for 1 hour. After being washed with PBS-Tween20
for 3 times, the plate was analyzed with a fluorescence microplate
counter (Flexstation III, Molecular Device).
PARP Enzymatic Assay (Following the Manual of HT Universal
Colorimetric PARP1 Assay Kit).
Histone proteins were coated on a 96-well plate and incubated
overnight at 4.degree. C. After be washed 3 times with 200 ul PBST
solution, the plate was blocked with a blocking solution and
incubated for 30 min at room temperature, and then washed with PBST
solution 3 times. A compound to be tested was treated and added to
the plate. Thereafter, 20 .mu.l of diluted PARP1 (1 nM) or 20 .mu.l
of PARP2 (3 nM) solution was added into the reaction system and
incubated for 1 or 2 hours. 50 ul of streptavidin-HRP mixture
(1:50) was added into the plate and incubated for 30 min at room
temperature. The plate was then washed with three times with PBST
buffer. 100 .mu.l of (HRP) (Chemiluminescent substrate A and
substrate B (1:1)) was added into the plate, and the plate was
immediately read on a microplate reader (Envision,
PerkinElmer).
Anti-Proliferation Assay
MDA-MB-436 and MDA-MB-231 cells were seeded in 96-well plates at
the density of 500 and 2000 cells per well respectively and
cultured overnight in a medium RPMI1640 supplemented with 10% (v/v)
FBS and 1% (v/v) Penicillin-Streptomycin. After adding a compound
to be tested, the cells were treated for 8 days. Cellular
viabilities were measured by CCK8 kit following the specific
method: adding 10 ul CCK8 reagent each well and incubating for 3
hours at 37.degree. C. in 5% CO2 incubator. After shaking for 10
min, the optical density values (OD) were measured at 450 nm by
Flexstation III (Molecular Device).
For the compound combination test (in combination with drugs for
DNA damages), the PF50 value is calculated to measure a synergetic
effect of a drug. PF50=[IC50 of a tested compound]/[IC50 of the
tested compound at a fixed conc. of a drug for DNA damages].
Temozolomide (TMZ) was used as the drug for DNA damages in this
study.
The data of PARP-1 enzymatic inhibition IC.sub.50 and cellular
PARylation EC.sub.50 of the compounds of this invention were
provided in Table I below. Compounds with IC.sub.50 between 1 nM to
100 nM were designated as +++; compounds with IC.sub.50 between 101
nM to 1000 nM were designated as ++, and compounds with IC.sub.50
above 1000 nM were designated as +.
TABLE-US-00001 TABLE 1 Tested/ Example Title IC.sub.50 EC.sub.50
Compounds (nM) (nM) ABT-888 +++ +++ MK-4827 +++ +++ BMN-673 +++ +++
1 +++ ++ 2 +++ +++ 3 +++ +++ 4 +++ +++ 5 +++ +++ 6 +++ +++ 7 +++
+++ 8 +++ ++ 9 +++ +++ 10 +++ +++ 11 +++ ++ 12 +++ +++ 13 +++ ++ 14
+++ +++ 15 +++ +++ 16 +++ +++ 17 +++ ++ 18 +++ +++ 19 +++ +++ 20
+++ +++ 21 +++ +++ 22 +++ +++ 23 +++ +++ 24 +++ ++ 25 +++ +++ 26
+++ ++ 27 +++ +++ 28 +++ +++ 29 +++ +++ 30 +++ +++ 31 +++ +++ 32
+++ +++ 33 +++ ++ 34 +++ ++ 35 +++ ++ 36 +++ ++ 37 +++ + 38 ++ + 39
+++ ++ 40 +++ + 41 ++ + 42 +++ ++ 43 +++ ++ 44 ++ ++ 45 ++ + 46 ++
+ 47 +++ + 48 +++ +++ 49 +++ ++ 50 ++ + 64 +++ ++ 65 +++ +++ 66 +++
+++ 67 +++ +++ 68 +++ +++ 69 +++ +++ 70 +++ +++ 71 +++ +++ 72 +++
+++ 73 +++ +++ 74 +++ ++ 75 +++ ++ 76 +++ +++ 77 +++ +++ 78 +++ +++
79 +++ +++ 80 +++ +++ 81 +++ +++ 82 +++ +++ 83 +++ +++ 84 +++ +++
85 +++ +++ 86 +++ +++ 87 +++ ++ 88 +++ +++ 89 +++ ++ 90 +++ +++ 91
+++ +++ 92 +++ +++ 93 +++ +++ 94 +++ ++ 95 +++ +++ 96 +++ +++ 97
+++ ++ 98 +++ ++ 99 +++ +++ 100 +++ +++ 101 +++ ++ 102 +++ ++ 103
+++ ++ 104 +++ +++ 105 +++ +++ 106 +++ ++ 107 +++ +++ 108 +++ +++
109 +++ ++ 110 +++ ++ 111 +++ +++ 112 +++ +++ 113 +++ +++ 114 +++
+++ 115 +++ +++ 116 +++ +++
* * * * *